ES2622566T3 - N- (Pyridin-2-yl) pyrimidin-4-amine derivatives containing a sulfoximin group - Google Patents

Abstract

A compound of the general formula (I) ** Formula ** in which R 1 represents a group selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, heterocyclyl, phenyl, heteroaryl, C 1 -C 3 alkyl or heteroaryl alkyl C1-C3-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C1-C3 alkyl-, C1- alkoxy C6-, C1-C3 fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, - OP (O) (OH) 2, -C (O) OH, -C (O) NH2; R2 represents a group selected from ** Formula ** R3, R4 independently represent each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C1 alkyl -C3-, C1-C3 alkoxy-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-; R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9, - C (O) NR10R11, -P (O) (OR12) 2 , -CH2OP (OR12) 2, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C1-C6- alkyl group, C3-C7- cycloalkyl, heterocyclyl-, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R6, R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C1-C3 alkyl-, C1-C3 alkoxy-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R8 represents a group selected from a) a C1-C6 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino- , Nmethyl- N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2-C3 alkynyl- , C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C3-C7- cycloalkyl, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen , hydroxy, C1-C3 alkyl, C1-C3 alkoxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1- fluoroalkoxy C3-; b) a C3-C7- cycloalkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino- , N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, C1-C3 haloalkyl, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2-C3 alkynyl- ; c) a heterocyclyl- group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2-C3 alkynyl; d) a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; e) a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; f) a phenyl-C1-C3-alkyl group, wherein the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino -, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; g) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino -, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; h) a C3-C6-cycloalkyl-C1-C3-alkyl group, wherein the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-alkyl C3-, C1-C3- alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy; i) a heterocyclyl-C1-C3-alkyl group, wherein the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-C3 alkyl-, C1-C3 alkoxy- , halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R9 represents a group selected from C1-C6- alkyl, halo-C1-C3- alkyl, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, of identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-alkyl C1-C3-, C1-C3- fluoroalkoxy; R10, R11 independently represent each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said C1-C6- alkyl group, C3- cycloalkyl C7-, heterocyclyl, phenyl, benzyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino- , dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, or R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine; R12 represents a group selected from hydrogen, C1-C4 alkyl or benzyl, and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

Description

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N- (Pyridin-2-yl) pyrimidin-4-amine derivatives containing a sulfoximin group

The present invention relates to disubstituted N- (pyridin-2-yl) pyrimidin-4-amine derivatives containing a sulfoximin group of general formula (I), as described and defined herein, and methods for its preparation. , its use in the treatment and / or prophylaxis of various disorders, particularly hyperproliferative disorders and / or infectious diseases induced by viruses and / or cardiovascular diseases.

Proteins of the family of cyclin-dependent kinases (CDK) consist of members that are fundamental regulators of the cell cycle (CDk of the cell cycle), which participate in the regulation of gene transcription (CDK of transcription) and of members with other functions. To exert its effects, CDKs must be activated, which can occur through association with a regulatory subunit, which is usually a cyclin. The cell cycle CDKs, which include the CDK1 and cyclin B complex, the CDK2 and cyclin A complex, the CDK2 and cyclin E complex, the CDK4 complex and cyclin D and the complex of the CDK6 and cyclin D, are activated consecutively to participate in the cell cycle. Transcription CDKs, which include the CDK9 and cyclin T complex and the CDK7 and cyclin H complex, regulate the activity of RNA polymerase II when the carboxyl-end domain (CTD) is phosphorylated. The positive transcription factor b (P-TEFb) is a CDK9 heterodimer and one of four possible cyclines, cyclin T1, cyclin K, cyclin T2a or cyclin T2b.

While the CDK9 (identification of the NCBI 1025 gene bank) only participates in the regulation of transcription, the CDK7 also participates in the regulation of the cell cycle, as a kinase that activates other CDKs (CAK).

The transcription of the genes by RNA polymerase II begins when the complex is assembled prior to the start in the promoter region, after which the serine residues 5 and 7 of the CTD are phosphorylated by the CDK7 / cyclin H. In most In genes, RNA polymerase II stops transcribing the mRNA once 20-40 nucleotides have moved along the DNA that serves as a template. This pause made by RNA polymerase II near the promoter is mediated by negative factors for the continuation of transcription, and it is recognized that it is an important control mechanism to regulate the expression of genes that are rapidly induced in response to various stimuli ( Cho et al., Cell Cycle, 9, 1697, 2010). P-TEFb plays a crucial role in resolving the pause that is induced near the promoter, as it mediates the transition to a state of continued production, for which the serine residue of CTD 2 is phosphorylated and phosphorylate and inactivate the negative factors for the continuation of transcription.

The activity of P-TEFb itself is regulated by various mechanisms. Approximately half of the P-TEFb in the cells takes the form of an inactive complex with the small 7SK nuclear RNA (abbreviated 7SK RNA), the 7-related protein (LARP7 / PIP7S) and the proteins that can be induced by hexamethylene bis-acetamide 1 and 2 (HEXIM1 / 2, He et al., Mol. Cell, 29, 588, 2008). The remaining portion of P-TEFb takes the form of an active complex that contains a protein comprising a domain with bromine Brd4 (Yang et al., Mol. Cell, 19, 535, 2005). Through an interaction with acetylated histones, Brd4 recruits P-TEFb into the chromatin areas where gene transcription is to occur. Through an alternative interaction with the positive and negative regulators, the P-TEFb is maintained in a functional balance. The P-TEFb bound to the complex with the 7SK siRNA constitutes a reserve from which the active P-TEFb can be released based on the demand for cell transcription and cell proliferation (Zhou and Yik, Microbiol. Mol. Biol. Rev., 70, 646, 2006). In addition, the activity of P-TEFb is regulated by various modifications that occur after translation, which may include phosphorylation, dephosphorylation, ubiquitination and acteylation (a review can be found in Cho et al., Cell Cycle, 9, 1697, 2010).

A deregulated activity of the CDK9 kinase can cause a lack of regulation in the P-TEFb heterodimer, which can be observed in the context of various pathological disorders in humans, such as hyperproliferative diseases (e.g., cancer), infectious diseases induced by viruses or cardiovascular diseases:

Cancer is considered to be a hyperproliferative disorder that is mediated by an imbalance between the proliferation and death of cells (apoptosis). Elevated levels of the antiapoptotic proteins of the Bcl-2 family can be found in various human tumors. These proteins result in prolonged survival of the tumor cells, which implies resistance to therapy. It was shown that, by inhibiting the kinase activity of P-TEFb, it was possible to reduce the transcription activity of RNA polymerase II, which resulted in a decline in the amount of antiapoptotic proteins, especially Mcl-1 and XIAP, which have a short half-life, with which the apoptosis of the tumor cells could be induced. Other diverse proteins that are associated with the phenotype of transformed tumors (such as Myc, NF-kB, transcripts that respond to genes or mitotic kinases) are proteins that have short half-lives or are encoded by transcripts with short half-lives , which are sensitive to reductions in RNA polymerase II activity that can be caused through P-TEFb inhibition (a review can be found in Wang and Fischer, Trends Pharmacol. Sci. 29, 302, 2008).

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Several viruses take advantage of the host cell transcription machinery to transcribe their own genome. For example, HIV-1 RNA polymerase II is recruited to the promoter region in the virus LTR. The virus transcription activating protein (Tat) binds to nascent virus transcripts, which results in the cancellation of the pause in the activity of RNA polymerase II that is induced near the promoter. In this process, P-TEFb is recruited, which is responsible for promoting the continuation of transcription. In addition, the Tat protein causes an increase in the fraction of the active P-TEFb, since thanks to its action, the proteins that inhibit the P-TEFb, HEXIM1 and 2, in the 7SK siRNA complex are replaced. Through recent studies, it has been shown that inhibition of the kinase activity of P-TEFb is sufficient to block HIV-1 replication, and that, for this, concentrations of non-resulting kinase inhibitors can be employed Toxic to host cells (a review can be found in Wang and Fischer, Trends Pharmacol. Sci. 29, 302, 2008). Similarly, the recruitment of protein-mediated P-TEFb from other viruses, such as the Epstein-Barr virus that is associated with cancer B cells, where EBNA2 nuclear antigenic protein interacts with P-TEFb has been described ( Bark-Jones et al., Oncogene, 25, 1775, 2006), and the human T-cell lymphotropic virus type 1 (HTLV-1), where the Tax transcription activator is responsible for the recruitment of P-TEFb (Zhou et al., J. Virol. 80, 4781,2006).

Cardiac hypertrophy, which is the adaptive response of the heart to mechanical overload and pressure (which may occur in the presence of hemodynamic stress, for example, hypertension or myocardial infarction), can result in heart failure and Long term death. It has been shown that cardiac hypertrophy is associated with an increased transcription activity and a higher phosphorylation of the RNA polymerase II CTD in cardiac muscle cells. It was discovered that P-TEFb is activated when the inactive complex is dissociated with the 7SK and HEXIM1 and 2 rRNA. Based on these findings, it can be inferred that the pharmacological inhibition of P-TEFb kinase activity could serve as a therapeutic approach to treat cardiac hypertrophy (a review can be found in Dey et al., Cell Cycle 6, 1856, 2007).

In summary, based on the abundant evidence available, it can be concluded that the selective inhibition of the activity of the CDK9 kinase in the P-TEFb heterodimer (comprising a CDK9 kinase and one of the following cyclin: the cyclin T1, the cyclin K, cyclin T2a or cyclin T2b) represents an innovative approach to treat diseases such as cancer, diseases caused by viruses and / or heart disease. The CDK9 belongs to a family that comprises at least 13 closely related kinases, of which those belonging to the subgroup of the cell cycle CDKs fulfill various functions in the regulation of cell proliferation. Therefore, it is logical to expect the inhibition of cell cycle CDKs (for example, CDK1 / cyclin B, CDK2 / cyclin A, CDK2 / cyclin E, CDK4 / cyclin D or CDK6 / cyclin D) and of the CDK9 it affects the tissues that present a normal proliferation, such as the intestinal mucosa, the lymphatic and hematopoietic organs and the reproductive organs. To maximize the therapeutic range of CDK9 kinase inhibitors, molecules that have a high selectivity for CDK9 are needed.

CDK inhibitors in general and CDK9 inhibitors in particular are described in a number of different publications: in WO200812970 and in WO200812971 2,4-disubstituted aminopyrimidines are described which can be used as CDK inhibitors in general. It is also mentioned that some of these compounds may act as selective inhibitors of CDK9 (WO200812970) and as inhibitors of cDk5 (WO200812971), but no specific values for IC50 are provided on CDK9 (WO200812970) or on the CDK5 (WO200812971). These compounds do not contain a fluorine atom at position 5 of the pyrimidine nucleus.

In WO2008129080 4,6-disubstituted aminopyrimidines are disclosed and these compounds are shown to have inhibitory effects on the activity of various protein kinases, such as CDK1, CDK2, CDK4, CDK5, CDK6 and CDK9 , with a preference for inhibition of CDK9 (example 80).

WO2005026129 discloses 4,6-disubstituted aminopyrimidines and demonstrates that these compounds have an inhibitory effect on the protein kinase activity of different protein kinases, in particular CDK2, CDK4 and CDK9.

WO2011116951 discloses substituted triazine derivatives as selective inhibitors of CDK9.

WO2012117048 discloses substituted triazine derivatives as selective inhibitors of CDK9.

WO2012117059 discloses substituted pyridine derivatives as selective inhibitors of CDK9.

WO2012143399 discloses substituted 4-aryl-N-phenyl-1,3,5-triazin-2-amines as selective inhibitors of CDK9.

EP1218360 B1, which corresponds to documents US2004116388A1, US7074789B2 and WO2001025220A1, describes triazine derivatives that can be used as kinase inhibitors, but no potent or selective inhibitors of CDK9 are described.

WO2008079933 discloses derivatives of aminopyridines and aminopyrimidines that can be used as inhibitors of CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9 .

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WO2011012661 describes derivatives of useful aminopyridines as inhibitors of CDKs.

WO2011026917 discloses carboxamides derived from substituted 4-phenylpyridin-2-amines as CDK9 inhibitors.

WO2012066065 discloses phenyl-heteroaryl amines as CDK9 inhibitors. A selectivity by CDK9 is preferred over other CDK isoforms, however, the disclosure of CDK inhibition data is confined to cDk 9. Bicyclic ring systems attached to the C4 position of the pyrimidine nucleus are not described. Within the group linked to the C4 of the pyrimidine nucleus, the alkoxy phenyls may be referred to as encompassed, but there is no suggestion of a specific substitution pattern characterized by a fluorine atom attached to the C5 of the pyrimidine ring, and a C2 pyrimidine aniline , exhibiting a substituted sulfonyl-methylene group in meta position. The compounds shown in the examples typically exhibit a substituted cycloalkyl group such as R 1 but not phenyl.

WO2012066070 discloses 3- (aminoaryl) -pyridine compounds as CDK9 inhibitors. The biaryl nucleus necessarily consists of two heteroaromatic rings.

WO2012101062 discloses substituted bi-heteroaryl compounds exhibiting a 2-aminopyridine nucleus as CDK9 inhibitors. The biaryl nucleus necessarily consists of two heteroaromatic rings.

WO2012101063 discloses carboxamides derived from substituted 4- (heteroaryl) -pyridin-2-amines as CDK9 inhibitors.

WO 2012101064 discloses biaryl N-acyl pyrimidine compounds as CDK9 inhibitors.

WO 2012101065 discloses biaryl pyrimidine compounds as CDK9 inhibitors. The biaryl nucleus necessarily consists of two heteroaromatic rings.

WO 2012101066 discloses biaryl pyrimidine compounds as CDK9 inhibitors. The R1 substitution of the amino group attached to the heteroaromatic nucleus is confined to non-aromatic groups, but does not cover substituted phenyls. Additionally, the biaryl nucleus necessarily consists of two heteroaromatic rings.

WO 2013037896 discloses disubstituted 5-fluoropyrimidines as selective inhibitors of CDK9.

WO 2013037894 discloses disubstituted 5-fluoropyrimidine derivatives containing a sulfoximin group as selective inhibitors of CDK9.

In Wang et al. (Chemistry and Biology 2010, 17, 1111-1121) 2-anilino-4- (thiazol-5-yl) pyrimidines are described which can be used as inhibitors of transcription CDKs, which exhibit anticancer activity in various animal-based models .

WO2004009562 discloses substituted triazines that can be used as kinase inhibitors. Data on certain compounds that inhibit CDK1 and CDK4 are provided, but no information is provided about CDK9.

WO2004072063 describes substituted heteroaryl pyrroles (pyrimidines and triazines) that can be used as protein kinase inhibitors such as ERK2, GSK3, pKa or CDK2.

WO2010009155 discloses screening of triazine and pyrimidine derivatives that can be used as inhibitors of histone deacetylase and / or cyclin-dependent kinases (CDK). Data are provided on certain compounds that can inhibit CDK2.

WO2003037346 (which corresponds to US7618968B2, US7291616B2, US2008064700A1 and US2003153570A1) refers to aryl triazines and their uses, which include inhibition of the activity of beta acyltransferase from lysophosphatidic acid (LPAAT-beta) and LPAAT-beta) the proliferation of certain tumor cells.

WO2005037800 discloses sulfoximin substituted aniline-pyrimidines as inhibitors of VEGFR and CDK kinases, in particular VEGFR2, CDK1 and CDK2, which do not have an aromatic ring directly attached to the pyrimidine ring and which have the sulfoximin group directly attached to the aniline group. CDK9 data is not described.

WO2008025556 describes carbamyl sulfoximides that have a pyrimidine nucleus and are useful as kinase inhibitors. Information about the CDK9 is not provided.

WO2002066481 describes pyrimidine derivatives that can be used as inhibitors of cyclin-dependent kinases, but CDK9 is not mentioned and no information about it is provided.

WO2008109943 describes compounds that are phenyl aminopiri (mi) dynes and their use as kinase inhibitors, particularly as inhibitors of JAK2 kinase. Specific examples focus on compounds comprising pyrimidine nuclei.

WO2009032861 describes substituted pyrimidinyl amines that can be used as JNK kinase inhibitors. Specific examples focus on compounds comprising pyrimidine nuclei.

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WO2011046970 describes compounds that are amino-pyrimidines that can be used as inhibitors of TBKL and / or IKK epsilon. Specific examples focus on compounds comprising pyrimidine nuclei.

WO2012142329 refers to amino-pyrimidine compounds as inhibitors of TBKL and / or IKK epsilon.

WO2012139499 describes urea substituted anilino-pyrimidines as inhibitors of different protein kinases.

Although several CDK inhibitors are known, there remains a need for selective CDK9 inhibitors that can be used to treat diseases such as hyperproliferative disorders, diseases caused by viruses and / or heart disease, presenting one or more advantages in relation to the compounds described in the technical background, such as:

• enhanced activity and / or effectiveness

• a kinase selectivity profile that is beneficial in the context of therapeutic applications

• an improved side effects profile, in which said side effects have reduced intensities, a reduced (cyto) toxicity, for example, by reduced inhibition of carbonic anhydrase

• improved physicochemical properties, such as solubility in aqueous body fluids, and aqueous formulations, for example, for intravenous administration

• better pharmacokinetic properties, for the purpose, for example, of reducing the dose or simplifying the dosing schedule

• manufacturing of easier drug substance, for example, by shorter synthetic routes or easier purification.

A particular object of the invention is to provide inhibitors of the CDK9 kinase which, in comparison with the compounds described in the technical background, exhibit greater selectivity for the CDK9 complex and the cyclin T1 (in relation to the CDK2 complex and cyclin E).

Another object of the invention is to provide CDK9 kinase inhibitors that have increased potency in the context of inhibition of CDK9 activity (which could be demonstrated through an IC50 with a lower value on CDK9 / cyclin T1) , in comparison with the compounds described in the technical background.

Another object of the invention is to provide inhibitors of CDK9 kinase that show increased potency to inhibit CDK9 activity at high concentrations of aTp compared to compounds known in the prior art.

Another object of the invention is to provide CDK9 kinase inhibitors, which show improved antiproliferative activity in tumor cell lines such as HeLa compared to the compounds known in the prior art.

In addition, it is also an objective of the present invention to provide CDK9 kinase inhibitors, which, in comparison to the compounds known in the prior art, are very selective for CDK9 / Cyclin T1 compared to CDK2 / Cyclin E, and / or that show increased potency to inhibit CDK9 activity and / or show enhanced antiproliferative activity in tumor cell lines such as HeLa and / or show increased potency to inhibit CDK9 activity at high concentrations of ATP compared to compounds known from the prior art.

The present invention relates to compounds of general formula (I)

R3

image 1

I

H

(I)

in which

R1 represents a group selected from C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, phenyl-

C1-C3- or heteroaryl-C1-C3- alkyl,

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wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C 1 -C 3 alkyl, C 1 -C 6 alkoxy, fluoroalkoxy C1-C3-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, - OP (O) (OH) 2, -C (O) OH, -C (O ) NH2;

R2 represents a group selected from

image2

-R6

image3

■ R6

F

R3, R4 independently represent each other, a group selected from a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, halo-C1 alkyl -C3-, C1-C3 fluoroalkoxy;

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9, - C (O) NR10R11, -P (O) (OR12) 2 , -CH2OP (OR12) 2, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group It is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N -methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoralkoxy;

R6, R7 independently represent each other, a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C3 alkyl-, C1-C3 alkoxy-, halo-C1-C3 alkyl-, C1 fluoroalkoxy -C3-;

R8 represents a group selected from

a) a C1-C6 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N -acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-, C2-C3 alkenyl, C2-C3 alkynyl, C3- cycloalkyl C7-, heterocyclyl-, phenyl, heteroaryl, wherein said C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3- alkyl, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-;

b) a C3-C7- cycloalkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino- , N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2- alkynyl C3-;

c) a heterocyclyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy, C2-C3 alkenyl, C2-C3 alkynyl;

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d) a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-;

e) a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-;

f) a phenyl-C1-C3-alkyl group, the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino- , dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy;

g) a heteroaryl-C1-C3-alkyl group, the heteroaryl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino- , dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy;

h) a C3-C6-cycloalkyl-C1-C3-alkyl group, the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-C3 alkyl -, C1-C3- alkoxy, halo-C1-C3 alkyl, C1-C3 fluoroalkoxy;

i) a heterocyclyl-C 1 -C 3 alkyl group, the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy;

R9 represents a group selected from C1-C6- alkyl, halo-C1-C3- alkyl, C3-C7- cycloalkyl, heterocyclyl,

phenyl, benzyl or heteroaryl,

wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R10, R11 independently represent each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, or

R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine;

R12 represents a group selected from hydrogen, C1-C4- or benzyl alkyl,

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

The present invention relates to compounds of general formula (I)

R3

image4

I

H

(I)

in which

R1 represents a group selected from C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, phenyl-

C1-C3- or heteroaryl-C1-C3- alkyl,

wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C1-C3 alkyl-, C1-C6 alkoxy-

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R2

, C1-C3 fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, - OP (O) (OH) 2, -C (O) OH, -C (O) NH2;

represents a group selected from

image5

-R6

image6

-R6

F

R3, R4 independently represent each other, a group selected from a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, halo-C1 alkyl -C3-, C1-C3 fluoroalkoxy;

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9, - C (O) NR10R11, -P (O) (O) 2 , -CH2OP (O) 2, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl, phenyl, heteroaryl, wherein said C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R6, R7 independently represent each other, a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C3 alkyl-, C1-C3 alkoxy-, halo-C1-C3 alkyl-, C1 fluoroalkoxy -C3-;

R8 represents a group selected from

a) a C1-C6- alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-, C2-C3 alkenyl, C2-C3 alkynyl, C3 cycloalkyl alkyl -C7-, heterocyclyl, phenyl, heteroaryl, wherein said C3-C7 cycloalkyl group, heterocyclyl, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, alkyl C1-C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

b) a C3-C7- cycloalkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino- , N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2- alkynyl C3-;

c) a heterocyclyl- group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2-C3 alkynyl;

d) a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-,

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C1-C3 fluoroalkoxy-, C1-C3 alkoxy;

e) a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-;

f) a phenyl-C1-C3-alkyl group, the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino- , dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy;

g) a heteroaryl-C1-C3-alkyl group, the heteroaryl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino- , dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy;

h) a C3-C6-cycloalkyl-C1-C3-alkyl group, the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-C3 alkyl -, C1-C3- alkoxy, halo-C1-C3 alkyl, C1-C3 fluoroalkoxy;

i) a heterocyclyl-C 1 -C 3 alkyl group, the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy;

R9 represents a group selected from C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or

heteroaryl,

wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R10, R11 independently represent each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, or

R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine;

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

The compounds according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds of the formula cited herein below which are comprised in the formula (I ) and the salts, solvates and solvates of the salts thereof, and the compounds that are comprised by formula (I) and are referred to herein as exemplary embodiments and the salts, solvates and solvates of the salts thereof, wherein the compounds that are comprised by formula (I) and are mentioned hereinbelow are not salts, solvates and solvates of the salts.

The compounds according to the invention may exist, depending on their structure, in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and the respective mixtures thereof. Stereoisomerically pure constituents can be isolated in known ways from said mixtures of enantiomers and / or diastereomers.

If the compounds according to the invention could be found in tautomeric forms, the present invention comprises all tautomeric forms.

In addition, the compounds of the present invention may exist in free form, for example, as a free base, or as a free acid, or as a zwitterion, or they may exist in the form of a salt. Said salt may be any salt, both an organic or inorganic addition salt, particularly any physiologically acceptable organic or inorganic addition salt, particularly any physiologically acceptable organic or inorganic addition salt commonly used in pharmacy.

The salts that are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. However, salts which are not suitable for pharmaceutical applications, but which, for example, can be used for the isolation or purification of the compounds according to the invention are also included.

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The term "physiologically acceptable salt" refers to a relatively non-toxic organic or inorganic acid addition salt of a compound of the present invention, for example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

The physiologically acceptable salts of the compounds according to the invention comprise acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example, salts of hydrochloric acid, hydrobromic acid, iodhydric acid, sulfuric acid, bisulfuric acid, phosphoric acid, nitric acid or with an organic acid, such as, for example, formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauryl, benzoic, salicylic, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid , cinnamic, cyclopentanpropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picrico, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, paraphenonic, tonic, sulfonic, biphenesonic, tonic, sulfonic, tonic, sulfonic, biphenolic , methanesulfonic, 2-naphthalene sulfonic, naphthalindisulfonic, camphorsulfonic, citric, tartaric, stearic, lactic, oxalic, malonic, succ inico, malico, adipico, alginico, maleic, fumarole, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric or thiocyanic, for example.

Physiologically acceptable salts of the compounds according to the invention also comprise salts of conventional bases, by way of preferred examples, alkali metal salts (for example, sodium and potassium salts), alkaline earth metal salts (for example, calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with between 1 and 16 C atoms, by way of preferred examples, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine , dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol, tris (hydroxymethyl) aminomethane, 1-aminopanodium, 1-aminopanodium, 1-aminopanodium, 1-aminopanodyl -amino-2,3,4-butanotriol. In addition, the compounds according to the invention can form salts with a quaternary ammonium ion that can be obtained by quaternizing a basic group containing nitrogen with agents such as lower alkylhalides such as, for example, methyl, ethyl, propyl, and butylchlorides, -bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkylhalides such as benzyl and phenethyl bromides and others. Examples of suitable quaternary ammonium ions are tetramethylammonium, tetraethylammonium, tetra (n-propyl) ammonium, tetra (n-butyl) ammonium or N-benzyl-N, N, N-trimethylammonium.

The present invention includes all possible salts of the compounds of the present invention as isolated salts, or as any mixture of said salts, in any proportion.

The term solvates is used in the invention for those forms of the compounds according to the invention that form a complex with the solvent molecules by coordination in solid or liquid state. Hydrates are a special form of solvates in which coordination takes place with water. Hydrates are preferred as solvates in the present invention.

The invention also includes all suitable isotopic variants of a compound of the invention. An isotopic variant of a compound of the invention is defined as one in which at least one atom is replaced by an atom with the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as, for example, 2H (deuterium), 3H (tritium) , 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl,

82Br, 123I, 124I, 129I and 131I, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes are incorporated, such as, for example, 3H or 14C, are useful in studies of tissue distribution of drugs and / or substrates. Tritiated and carbon isotopes 14, for example, 14C, are particularly preferred because of their ease of preparation and detectability. In addition, substitution with isotopes, such as, for example, deuterium may offer certain therapeutic advantages resulting from its high metabolic stability, for example, high in vivo half-life or reduced dosage requirements and therefore may be preferred in some circumstances. Isotopic variants of a compound of the invention can generally be prepared by conventional procedures known to those skilled in the art, such as, for example, by means of the illustrative procedures or by means of preparations described in the examples below, using the variants appropriate isotopics of the appropriate reagents.

Additionally, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, as single polymorphs, or as a mixture of more than one polymorph, in any proportion.

Accordingly, the present invention includes all possible salts, polymorphs, hydrates, solvates thereof, and diastereoisomeric forms of the compounds of the present invention as simple salt, polymorph, hydrate, solvate, thereof, or diastereoisomeric form, or as a mixture of more than one salt, polymorph, hydrate, solvate, thereof, or diastereoisomeric form in any proportion.

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For the purposes of the present invention, the substituents have the following meanings, unless otherwise specified:

The term "halogen", "halogen atom" or "halo" represents fluorine, chlorine, bromine and iodine atoms, particularly chlorine or fluorine atoms, preferably fluorine atoms.

The term "alkyl" represents a linear or branched alkyl radical with the amount of carbon atoms specifically indicated, for example, in C1-C10, one, two, three, four, five, six, seven, eight, nine or ten atoms carbon, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ferc-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, 2-methylbutyl, 1 - methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3- dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl. If the amount of carbon atoms is not specifically indicated, the term "alkyl" represents a linear or branched alkyl radical which, as a general rule, has between 1 and 9, particularly between 1 and 6, preferably between 1 and 4 carbon atoms . Particularly, the alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms ("C1-C6 alkyl"), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, ferc-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl. Preferably, the alkyl group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), methyl, ethyl, n-propyl or isopropyl.

The expression "C2-C3 alkenyl" should be understood as preferably meaning a linear or branched monovalent hydrocarbon group, containing a double bond, and having 2 or 3 carbon atoms ("C2-C3 alkenyl"). Said alkenyl group is, for example, a vinyl, allyl, (E) -2-methylvinyl, (Z) -2-methylvinyl or isopropenyl group.

The term "C2-C3 alkynyl" should be understood as preferably meaning a linear monovalent hydrocarbon group containing a triple bond, and containing 2 or 3 carbon atoms. Said C2-C3 alkynyl group is, for example, an ethynyl, prop-1-ynyl or prop-2-inyl group.

The term "C3-C7 cycloalkyl" should be understood as preferably meaning a monovalent monovalent saturated hydrocarbon ring containing 3, 4, 5, 6 or 7 carbon atoms. Said C3-C7- cycloalkyl group is, for example, a monocyclic hydrocarbon ring, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group. Said cycloalkyl ring is non-aromatic but may optionally contain one or more double bonds, for example, cycloalkenyl, such as, for example, a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl group, in which the bond between said ring with the rest of The molecule can be made with any carbon atom of said ring, whether saturated or unsaturated. In particular, said cycloalkyl group is a C4-C6 cycloalkyl group, a C5-C6 cycloalkyl group or a cyclohexyl group.

The term "C3-C5 cycloalkyl" should preferably be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring containing 3, 4 or 5 carbon atoms. In particular said C3-C5 cycloalkyl group is a monocyclic hydrocarbon ring such as a cyclopropyl, cyclobutyl or cyclopentyl group. Preferably said "C3-C5 cycloalkyl" group is a cyclopropyl group.

The term "C3-C6 cycloalkyl" should preferably be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring containing 3, 4, 5 or 6 carbon atoms. In particular said C3-C6 cycloalkyl group is a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term "C3-C6 cycloalkyl-C1-C3- alkyl" group should preferably be understood as meaning a C3-C6 cycloalkyl group as defined above, in which one of the hydrogen atoms is replaced by an alkyl group. C1-C3-, as defined above, linking the C3-C6-cycloalkyl-C1-C3-alkyl- group to the molecule. Particularly, the "C3-C6 cycloalkyl-C1-C3-alkyl-" is a "C3-C6-cycloalkyl-C1-C2- alkyl", preferably it is a group "C3-C6-methyl- cycloalkyl."

The term "heterocyclyl" should be understood as preferably meaning a monovalent or partially unsaturated monovalent or partially unsaturated hydrocarbon ring containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms and also containing 1, 2 or 3 groups containing heteroatoms selected from oxygen, sulfur, nitrogen. Particularly, the term "heterocyclyl" should be understood as preferably meaning a "heterocyclic ring of between 4 and 10 members."

The term "4- to 10-membered heterocyclic ring" should be understood as preferably meaning a monovalent or partially unsaturated monovalent or partially unsaturated hydrocarbon ring containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and which also contains 1.2 or 3 groups containing heteroatoms selected from oxygen, sulfur, nitrogen. A C3-C9-heterocyclyl should be understood as referring to a heterocyclyl containing at least 3, 4, 5, 6, 7, 8 or 9 carbon atoms and additionally at least one heteroatom as ring atoms. Consequently, in case of a heteroatom, the ring is between 4 and 10 members, in case of two heteroatoms the ring is between 5 and 11 members and in case of three heteroatoms the ring is between 6 and 12 members.

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Said heterocyclic ring is, for example, a monocyclic heterocyclic ring such as, for example, an oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 1,4-dioxanyl, pyrrolinyl, pyrrolinyl, , piperidinyl, morpholinyl, 1,3-dithianyl, thiomorpholinyl, piperazinyl, or quinuclidinyl. Optionally, said heterocyclic ring may contain one or more double bonds, for example, a 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1 H-pyrrolyl, 1,3-dioxolyl, 4H-1,3,4 group. -thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3-dihydrothienyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, or 4H-1,4-thiazinyl, or may Be benzo condensed.

Particularly a C3-C7 heterocyclyl should be understood as referring to a heterocyclyl containing at least 3, 4, 5, 6 or 7 carbon atoms and additionally at least one heteroatom as ring atoms. Consequently, in the case of a heteroatom the ring is between 4 and 8 members, in the case of two heteroatoms the ring is between 5 and 9 members and in the case of three heteroatoms the ring is 6 to 10 members.

Particularly a C3-C6 heterocyclyl should be understood as referring to a heterocyclyl containing at least 3, 4, 5 or 6 carbon atoms and additionally at least one heteroatom as ring atoms. Consequently, in case of a heteroatom the ring is between 4 and 7 members, in case of two heteroatoms the ring is between 5 and 8 members and in case of three heteroatoms the ring is between 6 to 9 members.

Particularly, the term "heterocyclyl" should be understood as a heterocyclic ring containing 3, 4 or 5 carbon atoms, and 1, 2 or 3 of the groups containing heteroatoms that have been mentioned (a "heterocyclic ring between 4 and 8 members "), more particularly said ring may contain 4 or 5 carbon atoms, and 1, 2 or 3 of the groups containing heteroatoms that have been mentioned (a" 5- and 8-membered heterocyclic ring "), more particularly said heterocyclic ring is a "6-membered heterocyclic ring", which should be understood to contain 4 carbon atoms and 2 of the groups containing heteroatoms mentioned or 5 carbon atoms and one of the groups containing heteroatoms mentioned , preferably 4 carbon atoms and 2 of the groups containing heteroatoms mentioned above.

The term "heterocyclyl-C1-C3-alkyl" group should preferably be understood as meaning a heterocyclyl, preferably a 4 and 7 membered heterocyclyl ring, more preferably a 5 and 7 membered heterocyclyl ring, each as defined above. , in which one of the hydrogen atoms is replaced by a C1-C3-alkyl group, as defined above, which binds the heterocyclyl-C1-C3-alkyl group to the molecule. Particularly, the "heterocyclyl-C 1 -C 3 alkyl" is a "heterocyclyl-C 1 -C 2 alkyl", preferably it is a heterocyclyl methyl group.

The term "C1-C6 alkoxy-" should be understood as preferably meaning a monovalent saturated linear or branched hydrocarbon group of the formula -O-alkyl, wherein the term "alkyl" is as defined, for example, a Methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentyloxy, isopentyloxy, n-hexyloxy, or an isomer thereof. Particularly, the group "C1-C6 alkoxy-" is a "C1-C4 alkoxy-", "C1-C3 alkoxy-", methoxy, ethoxy, or propoxy, preferably a methoxy, ethoxy or propoxy group. More preferred is a "C1-C2- alkoxy" group, particularly a methoxy or ethoxy group.

The term "C1-C3- fluoroalkoxy" should be understood as preferably meaning a monovalent saturated linear or branched C1-C3-alkoxy group, as defined, wherein one or more of the hydrogen atoms is replaced, identically or different, for one or more fluorine atoms. Said C1-C3-fluoroalkoxy group is, for example, a 1,1-difluoromethoxy-, 1,1,1-trifluoromethoxy-, 2-fluoroethoxy-, 3-fluoropropoxy-, 2,2,2-trifluoroethoxy- or 3 group , 3,3-trifluoropropoxy-, particularly a "C1-C2- fluoroalkoxy-" group.

The term "alkylamino-" should be understood as preferably meaning an alkylamino group with a linear or branched alkyl group as defined. (C1-C3) alkylamino - for example, means a monoalkylamino group with 1, 2 or 3 carbon atoms, (C1-C6) -alkylamino- with 1, 2, 3, 4, 5 or 6 carbon atoms. The term "alkylamino-" comprises, for example, methylamino-, ethylamino-, n-propylamino-, isopropylamino-, tert-butylamino-, n-pentylamino- or n-hexylamino-.

The term "dialkylamino-" should be understood as preferably meaning an alkylamino group with two linear or branched alkyl groups as defined, which are independent of each other. (C1-C3) -dialkylamino- for example, represents a dialkylamino group with two alkyl groups, each having 1 to 3 carbon atoms per alkyl group. The term "dialkylamino-" comprises, for example: N, N-Dimethylamino-, N, N-Diethylamino-, N-Ethyl-N-methylamino-, N-Methyl-Nn-propylamino-, N-Isopropyl-Nn-propylamino -, Nt-Butyl-N-methylamino-, N-Ethyl-Nn-pentylamino- and Nn-Hexyl-N-methylamino-.

The term "cyclic amine" should be understood as preferably meaning a cyclic amine group. Preferably, a cyclic amine refers to a monocyclic group with 4 to 10, preferably 4 to 7 ring atoms of which at least one is nitrogen. Suitable cyclic amines are especially azetidine, pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, thiomorpholine, which may be optionally substituted with one or two methyl groups.

The expression "halo-C1-C3-alkyl" or, used synonymously, "halo-C1-C3-alkyl", should be understood as preferably meaning a monovalent saturated linear or branched hydrocarbon group in which the expression

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"C1-C3 alkyl" has been defined above, and in which one or more hydrogen atoms is replaced by a halogen atom, identically or differently, for example, halogen atoms independently of one another. Particularly, said halogen atom is fluorine. A preferred halo-C1-C3-alkyl group is a fluoro-C1-C3-alkyl group, for example, a group CF3, -CHF2, -CH2F, -CF2CF3, or -CH2CF3, preferably is -CF3.

The expression "phenyl-C1-C3-alkyl" should be understood as preferably meaning a phenyl group, in which one of the hydrogen atoms is replaced by a C1-C3-alkyl group, as defined above, which binds the phenyl-C1-C3-alkyl group to the molecule. Particularly, "phenyl-C 1 -C 3 alkyl" is a phenyl-C 1 -C 2 alkyl group, preferably benzyl.

The term "heteroaryl" should be understood as preferably meaning a monovalent ring system with 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "heteroaryl group of between 5 and 14 members "), particularly 5 (a" 5 member heteroaryl ") or 6 (a" 6 member heteroaryl ") or 9 (a" 9 member heteroaryl ") or 10 ring atoms (a" 10 heteroaryl " members "), and which contains at least one heteroatom that may be identical or different from the others, where said heteroatom is, for example, oxygen, nitrogen or sulfur, and may be monocyclic, bicyclic, or tricyclic, and also in each case It can be benzo-condensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl etc., and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothienyl bencisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc .; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc. Preferably, the heteroaryl is selected from monocyclic heteroaryl, 5-membered heteroaryl or 6-membered heteroaryl.

The term "5-membered heteroaryl" should be understood as preferably meaning a monovalent aromatic ring system with 5 atoms in the ring and containing at least one heteroatom that can be identical or different from the others, where said heteroatom is, by example, oxygen, nitrogen or sulfur. Particularly, "5-membered heteroaryl" is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl.

The term "6-membered heteroaryl" should be understood as preferably meaning a monovalent aromatic ring system with 6 atoms in the ring and containing at least one heteroatom that can be identical or different from the others, where said heteroatom is, by example, oxygen, nitrogen or sulfur. Particularly, "6-membered heteroaryl" is selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.

The term "heteroaryl-C1-C3-alkyl-" should be understood as preferably meaning a heteroaryl, 5-membered heteroaryl or 6-membered heteroaryl group, each as defined, wherein one of the hydrogen atoms is replaced by a C1-C3-alkyl group, as defined above, which binds the heteroaryl-C1-C3-alkyl group to the molecule. Particularly, "heteroaryl-C1-C3-alkyl-" is a heteroaryl-C1-C2-alkyl, pyridinyl-C1-C3-alkyl, pyridinylmethyl, pyridinylethyl, pyridinylpropyl, pyrimidinyl-C1-C3- alkyl, pyrimidinylmethyl, pyrimidinyl or pyrimidinylpropyl , preferably a pyridinylmethyl or pyridinylethyl or pyrimidinylethyl or pyrimidinylpropyl group.

As used herein, the term "leaving group" refers to an atom or group of atoms that is displaced in a chemical reaction as stable species carrying the bond electrons. Preferably, a leaving group is selected from the group comprising: halo, in particular chlorine, bromine or iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromobenzene) sulfonyloxy, (4-nitrobenzene) sulfonyl sulfonyl (2-nitro-benzene) -sulfonyloxy, (4-isopropyl-benzene) sulfonyloxy, (2,4,6-tri-isopropyl-benzene) -sulfonyloxy, (2,4,6-trimethyl-benzene) sulfonyloxy, (4 -ferc-butyl-benzene) sulfonyloxy,

benzenesulfonyloxy and (4-methoxybenzene) sulfonyloxy.

The term "C1-C10", as used throughout this text, for example, in the context of the definition of "C1-C10 alkyl" should be understood as preferably meaning an alkyl group with a finite amount of carbon atoms of between 1 and 10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It should also be understood that said term "C1-C10" should be construed as any sub-interval included therein, for example, C1-C10, C1-C9, C1-C8, C1-C7, C1-C6 C1-C5, C1-C4 , C1-C3, C1-C2, C2-C10, C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-

C3, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5-C9, C5-C8,

C5-C7, C5-C6, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9, C9-C10.

Similarly, the term "C1-C6", as used throughout this text, for example, in the context of the definition of "C1-C6 alkyl", "C1-C6 alkoxy" should be understood as which preferably means an alkyl group with a finite amount of carbon atoms of between 1 and 6, for example, 1, 2, 3, 4, 5 or 6 carbon atoms. In addition, it should be understood that said term "C1-C6" should be interpreted as any sub-interval comprised therein, for example, C1-C6 C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2- C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, C5-C6.

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Similarly, the term "C1-C3", as used herein, for example, in the context of the definition of "C1-C3 alkyl", "C1-C3 alkoxy" or "C1-C3 fluoroalkoxy" It should be understood as preferably an alkyl group with a finite amount of carbon atoms of between 1 and 3, for example, 1, 2 or 3 carbon atoms. In addition, it should be understood that said term "C1-C3" should be interpreted as any sub-interval comprised therein, for example, C1-C3, C1-C2, C2-C3.

Also, as used herein, the term "C3-C6", as used throughout this text, for example, in the context of the definition of "C3-C6 cycloalkyl", should be understood as being refers to a cycloalkyl group that has a finite number of carbon atoms between 3 and 6, that is, 3, 4, 5 or 6 carbon atoms. It should also be understood that said term "C3-C6" should be interpreted as any sub-interval within it, for example, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, C5-C6. In addition, the term "C3-C7", as used herein, for example, in the context of the definition of "C3-C7- cycloalkyl", should be understood as preferably meaning a cycloalkyl group with a finite amount of carbon atoms of between 3 and 7, for example, 3, 4, 5, 6 or 7 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms. In addition, it should be understood that said term "C3-C7" should be construed as any sub-interval included therein, for example, C3-C7, C3-C6, C3-C5, C3-C4, C4-C7, C4-C6, C4 -C5, C5-C7, C5-C6, C6-C7.

A symbol

/

in a union denotes the point of union in the molecule.

As used herein, the expression "one or more times", for example, in the definition of the substituents of the compounds of the general formulas of the present invention, means one, two, three, four or five times, particularly once, twice, three or four times, more particularly once, twice or three times, even more particularly once or twice.

When the plural form of the compounds, salts, hydrates, solvates and the like is used herein, this also includes a single compound, salt, isomer, hydrate, solvate or the like.

In another embodiment the present invention refers to compounds of general formula (I), in which

R1

R2

represents a group selected from C1-C6- alkyl, C3-C5- cycloalkyl,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C3 alkoxy, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, amines cyclics, -OP (O) (OH) 2, -C (O) OH, -C (O) NH2;

represents a group selected from> 8

image7

-R6

R

R

R '

R7

R3 represents a hydrogen atom, a fluorine atom or a chlorine atom, a C1-C3 alkyl group or a halo-C1-C3 alkyl group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9, - C (O) NR10R11, -P (O) (OR12) 2 , -CH2OP (OR12) 2, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group It is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N -methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R6, R7 independently represent each other, a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C3 alkyl-, C1-C3 alkoxy-, halo-C1-C3 alkyl-, C1 fluoroalkoxy -C3-;

R8 represents a group selected from

a) a C1-C6 alkyl group, which is optionally substituted with one or two or three substituents, so

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identical or different, selected from halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C3-C7- cycloalkyl group, heterocyclyl-, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or different, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cf. amines, halo-C1-C3 alkyl-, C1- fluoroalkoxy C3-;

b) a phenyl-C1-C3-alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-;

c) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-;

d) a C3-C6-cycloalkyl-C1-C3-alkyl group, wherein the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-alkyl C3-, C1-C3- alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy;

e) a heterocyclyl-C 1 -C 3 alkyl group, wherein the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy , halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R9 represents a group selected from C1-C6- alkyl, halo-C1-C3- alkyl, C3-C7- cycloalkyl, heterocyclyl,

phenyl, benzyl or heteroaryl,

wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R10, R11 represent, independently from each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl, benzyl, phenyl or heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, benzyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyl amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, or

R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine;

R12 represents a group selected from hydrogen or C1-C4 alkyl,

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In another embodiment the present invention refers to compounds of general formula (I), in which

R1 represents a group selected from C1-C6- alkyl, C3-C5- cycloalkyl,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C2 alkoxy-, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, amines cyclic, -OP (O) (OH) 2, -C (O) OH, -C (O) NH2;

R2 represents a group selected from

8

image8

R

6

R

i3

represents a hydrogen atom, a fluorine atom or a chlorine atom, or a C1-C3- alkyl group; represents a hydrogen atom or a fluorine atom;

R

4

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Four. Five

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9, -

C (O) NR10R11, -P (O) (O) 2, -CH2OP (O) 2, C1-C6 alkyl-, C3-C7 cycloalkyl-, heterocyclyl-, phenyl, heteroaryl, wherein said C1- alkyl group C6-, C3-C7- cycloalkyl, heterocyclyl-, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1-C3 alkyl-, C1-C3 alkoxy -, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R6, R7 independently represent each other, a group selected from a hydrogen atom, atom

fluorine, chlorine atom, C1-C3- alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R8 represents a group selected from

a) a C1-C6 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines , cyano, C1-C3- alkyl, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy, C1-C3- alkoxy, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C3- cycloalkyl group C7-, heterocyclyl, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, dialkylamino-, acetylamino-, N - methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

b) a phenyl-C1-C3-alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy;

c) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy;

d) a C3-C6-cycloalkyl-C1-C3-alkyl group, wherein the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-alkyl C3-, C1-C3- alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy;

e) a heterocyclyl-C 1 -C 3 alkyl group, wherein the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy , halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R9 represents a group selected from C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or

heteroaryl,

wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy;

R10, R11 independently represent each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl-, benzyl, phenyl or heteroaryl,

wherein said C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl, benzyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1- alkyl C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, or

R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine;

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In a preferred embodiment the present invention refers to compounds of general formula (I), in which

R1 represents a C1-C6-alkyl or C3-C5 cycloalkyl group,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, -OP (O) (OH) 2;

R2 represents a group selected from

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image9

R3 represents a hydrogen atom, fluorine atom or chlorine atom, a C1-C3-alkyl group or a C1-C3-fluoro-alkyl group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11,

-P (O) (OR12) 2, -CH2OP (OR12) 2 or C1-C3 alkyl-,

wherein said C1-C3 alkyl group is optionally substituted with a substituent, selected from - NH2, alkylamino-, dialkylamino-, or cyclic amines;

R6, R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom;

R8 represents a group selected from

a) a C1-C3 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, halo-C1-C3 alkyl;

b) a phenyl-C1-C3-alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C1-C3 alkyl -, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-;

c) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, cyano, C1-C3- alkyl, halo-C 1 -C 3 alkyl, C 1 -C 3 fluoroalkoxy, C 1 -C 3 alkoxy;

R9 represents a group selected from C1-C3 alkyl, halo-C1-C3 alkyl, or a benzyl group, where the phenyl group thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting in halogen, C1-C3- alkyl, C1-C3- alkoxy, -NH2, alkylamino-, dialkylamino;

R10, R11 independently represent each other, a group selected from hydrogen, C1-C3- alkyl, benzyl, or

R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine;

R12 represents a group selected from hydrogen or C1-C2-alkyl, and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In a preferred embodiment the present invention refers to compounds of general formula (I), in which

R 1 represents a C 1 -C 6 alkyl or C 3 -C 5 cycloalkyl group,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C6 alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, -OP (O) (OH) 2;

R2 represents a group selected from

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image10

R3 represents a hydrogen atom, fluorine atom or chlorine atom, or a C1-C3- alkyl group;

R4 represents a hydrogen atom or a fluorine atom;

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11,

-P (O) (O) 2, -CH2OP (O) 2 or C1-C3 alkyl-,

wherein said C1-C3 alkyl group is optionally substituted with a substituent, selected from - NH2, alkylamino-, dialkylamino-, or cyclic amines;

R6, R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom;

R8 represents a group selected from

a) a C1-C3 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, halo-C1-C3 alkyl;

b) a phenyl-C1-C3-alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C1-C3 alkyl -, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-;

c) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, cyano, C1-C3- alkyl, halo-C 1 -C 3 alkyl, C 1 -C 3 fluoroalkoxy, C 1 -C 3 alkoxy;

R9 represents a group selected from C1-C3 alkyl, C1-C3 haloalkyl, benzyl group, where the group

phenyl thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino;

R10, R11 independently represent each other, a group selected from hydrogen, C1-C3- alkyl, benzyl, or

R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine; and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In another preferred embodiment the present invention refers to compounds of general formula (I), in which

R1

R2

represents a C1-C6- alkyl group,

wherein said group is optionally substituted with a substituent, selected from the group consisting of C1-C3-, -NH2 alkoxy, alkylamino-, dialkylamino-, or cyclic amines; represents a group selected from

image11

R3 represents a hydrogen atom, fluorine atom or chlorine atom, or a methyl or trifluoromethyl group;

R4 represents a hydrogen atom or fluorine atom;

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11;

R6, R7 independently represent each other, a group selected from a hydrogen atom, atom

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of fluorine or chlorine atom;

R8 represents a C1-C3- alkyl group;

R9 represents a C1-C3- alkyl group, a benzyl group, or trifluoromethyl;

R10, R11 independently represent each other, a group selected from hydrogen, C1-C2 alkyl; and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In another preferred embodiment the present invention refers to compounds of general formula (I), in which

R1

R2

represents a C1-C6 alkyl group,

wherein said group is optionally substituted with a substituent, selected from the group consisting of C1-C3-, -NH2 alkoxy, alkylamino-, dialkylamino-, or cyclic amines; represents a group selected from

image12

R3 represents a hydrogen atom, fluorine atom or chlorine atom;

R4 represents a hydrogen atom or fluorine atom;

R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11;

R6, R7 independently represent each other, a group selected from a hydrogen atom, fluorine atom or chlorine atom;

R8 represents a C1-C3- alkyl group;

R9 represents a C1-C3- alkyl group, a benzyl group, or trifluoromethyl;

R10, R11 independently represent each other, a group selected from hydrogen, C1-C2 alkyl;

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In a particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which

R1 represents a C1-C3 alkyl group;

R2 represents a group

R3

R4

R5

R6

R7

R8

image13

represents a hydrogen atom or a chlorine atom, or a methyl or trifluoromethyl group;

represents a hydrogen atom;

represents a hydrogen atom;

represents a fluorine atom;

represents hydrogen;

represents a methyl group;

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In a particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which

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R1 represents a C1-C3- alkyl group; R2 represents a group

image14

R3 represents a hydrogen atom or a chlorine atom;

R4 represents a hydrogen atom;

R5 represents a group selected from a hydrogen atom, -C (O) R9;

R6 represents hydrogen, para-fluoro, or para-chloro, where for reference the point of attachment of R2 to the rest

of the molecule;

R7 represents hydrogen;

R8 represents a methyl group;

R9 represents a trifluoromethyl group;

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In another particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which

R1 represents a methyl or ethyl group;

R2 represents a 4-fluoro-2-methoxyphenyl group;

R3 represents a hydrogen atom or a chlorine atom, or a methyl or trifluoromethyl group;

R4 represents a hydrogen atom;

R5 represents a hydrogen atom;

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In another particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which

R1 represents a methyl group;

R2 represents a 4-fluoro-2-methoxyphenyl group;

R3 represents a hydrogen atom or a chlorine atom;

R4 represents a hydrogen atom;

R5 represents a hydrogen atom;

and the enantiomers, diasteromers, salts, solvates or solvate salts thereof.

In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a group selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, heterocyclyl, phenyl, heteroaryl, C 1 -C 3 alkyl - or heteroaryl-C1-C3 alkyl-,

wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C 1 -C 3 alkyl, C 1 -C 6 alkoxy, fluoroalkoxy C1-C3-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, - OP (O) (OH) 2, -C (O) OH, -C (O ) NH2.

In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a C 1 -C 3 alkyl group, C 3 -C 5 cycloalkyl, a 4- to 7-membered heterocyclic ring, phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-C1-C2-alkyl,

wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C 1 -C 2 alkyl, C 1 -C 3 alkoxy, fluoroalkoxy C1-C2-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines.

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In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a group selected from C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C3 alkoxy, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, amines cyclics, -OP (O) (OH) 2, -C (O) OH, -C (O) NH2.

In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a group selected from C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C2 alkoxy-, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, amines cyclics, -OP (O) (OH) 2, -C (O) OH, -C (O) NH2.

In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a phenyl or heteroaryl group,

wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C 1 -C 2 alkyl, C 1 -C 3 alkoxy, fluoroalkoxy C1-C2-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines.

In another embodiment, the present invention relates to compounds of general formula (I), in which R 1 represents a group selected from C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl,

wherein said group is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of hydroxy, C1-C2 alkoxy, halo C1-C2 alkyl, C1-C2 fluoroalkoxy, - NH2, - OP (O) (OH) 2, -C (O) OH, -C (O) NH2.

In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a group selected from methyl, ethyl, propan-2-yl, ferc-butyl, cyclopropyl, cyclohexyl or phenyl,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxyl or methoxy.

In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a group selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or phenyl C 1 -C 3 alkyl;

wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy or C1-C6 alkoxy.

In another embodiment the invention relates to compounds of formula (I), in which R 1 represents a group selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or phenyl C 1 -C 2 alkyl;

wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy or C1-C3 alkoxy.

In a preferred embodiment the present invention refers to compounds of general formula (I), in which R 1 represents a C 1 -C 6 alkyl or C 3 -C 5 cycloalkyl group,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, -OP (O) (OH) 2.

In a preferred embodiment the present invention refers to compounds of general formula (I), in which R 1 represents a C 1 -C 6 alkyl or C 3 -C 5 cycloalkyl group,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C6 alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, -OP (O) (OH) 2.

In another preferred embodiment the invention relates to compounds of formula (I), in which R 1 represents a C 1 -C 6 alkyl group,

wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C6 alkoxy-, -NH2, -OP (O) (OH) 2.

In another preferred embodiment the present invention refers to compounds of general formula (I), in which R 1 represents a C 1 -C 6 alkyl group,

wherein said group is optionally substituted with a substituent, selected from the group consisting of C1-C3-, -NH2 alkoxy, alkylamino-, dialkylamino-, or cyclic amines.

In another preferred embodiment the invention relates to compounds of formula (I), wherein R 1 represents a group selected from methyl, ethyl, propan-2-yl, cyclopropyl, ferc-butyl, cyclopentyl, cyclohexyl or phenyl,

wherein said group is optionally substituted with a substituent, selected from the group consisting of C1-C3-, -NH2 alkoxy, alkylamino-, dialkylamino-, or cyclic amines.

In another preferred embodiment the invention relates to compounds of formula (I), in which R 1 represents a group selected from methyl, ethyl, propan-2-yl, cyclopropyl, or ferc-butyl,

wherein said group is optionally substituted with a substituent, selected from the group consisting of C1-C3-, -NH2 alkoxy, alkylamino-, dialkylamino-, or cyclic amines.

In a preferred embodiment the present invention refers to compounds of general formula (I), in which R 1 represents a C 1 -C 6 alkyl group,

wherein said group is optionally substituted with a substituent, selected from the group consisting of hydroxy or -OP (O) (oH) 2.

In a particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which R 1 represents a C 1 -C 3 alkyl group.

In another particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which R 1 represents a methyl group.

In another particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which R 1 represents a methyl or ethyl group.

In another particularly preferred embodiment, the present invention refers to compounds of general formula (I), in which R 1 represents an ethyl group.

In another embodiment the invention relates to compounds of formula (I), in which R2 represents a group selected from

image15

-R6

R7

R7

R7

R7

image16

-R6

R

R7

R7

F

In another embodiment the invention relates to compounds of formula (I), in which R2 represents a group selected from

image17

-Rb

R

R

R

R7

In another embodiment the invention relates to compounds of formula (I), in which R2 represents a group selected from

image18

R

R

R7

image19

R6

R7

F

F

5

In a preferred embodiment the invention represents a group selected from

relate

with compounds of

formula (I), in which R2

image20

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R2 represents

image21

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R2 represents a 4-fluoro-2-methoxyphenyl group.

In another embodiment, the invention relates to compounds of formula (I), in which R3 and R4 independently represent each other, a group selected from a hydrogen atom, fluorine atom, chlorine atom, atom of bromine, cyano, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy.

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In another preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a hydrogen atom, fluorine atom or chlorine atom, a C1-C3 alkyl group or a C1-alkyl-fluoro group -C3- and R4 represents a hydrogen atom or a fluorine atom.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R3

represents a hydrogen atom, fluorine atom or chlorine atom, or a C1-C3- alkyl group, and R4 represents a

hydrogen atom or a fluorine atom.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R3

represents a hydrogen atom, fluorine atom or chlorine atom, or a methyl or trifluoromethyl group, and R4

It represents a hydrogen atom or a fluorine atom.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a hydrogen atom, fluorine atom or chlorine atom, and R4 represents a hydrogen atom or a fluorine atom.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a hydrogen atom or chlorine atom, or a methyl or trifluoromethyl group, and R4 represents a hydrogen atom.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a hydrogen atom or chlorine atom, and R4 represents a hydrogen atom.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a methyl or trifluoromethyl group, and R4 represents a hydrogen atom.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a hydrogen atom or a chlorine atom, and R4 represents a hydrogen atom.

In another embodiment, the invention relates to compounds of formula (I), in which R3 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano, C1-C3 alkyl- , C1-C3- alkoxy, halo-C1-C3 alkyl, C1-C3 fluoroalkoxy.

In another embodiment the invention relates to compounds of formula (I), in which R3 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C3- alkyl, C1-C3 alkoxy- , halo-C1-C3- alkyl, C1-C3- fluoroalkoxy.

In another embodiment the invention relates to compounds of formula (I), in which R3 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C2- alkyl, C1-C2 alkoxy- , halo-C1-C2- alkyl, C1-C2- fluoroalkoxy.

In a preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a hydrogen atom, fluorine atom or chlorine atom, a C1-C3 alkyl group or a halo-C1 alkyl group -C3.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a hydrogen atom, fluorine atom or chlorine atom, a C 1 -C 3 alkyl group or a fluoro-alkyl group

C1-C3.

In another preferred embodiment the invention relates to compounds representing a hydrogen atom, a C1-C3 alkyl group or a Cr-alkyl-fluoro group

of formula (I), in which R3 C3.

In another preferred embodiment the invention relates to compounds of formula (I), in which R 3 represents a C 1 -C 3 alkyl group or a C 1 -C 3 fluoro-alkyl group.

In another preferred embodiment the invention relates to compounds representing a fluoro-C1-C alkyl group.

In another preferred embodiment the invention relates to compounds representing a hydrogen atom or a C1-C3 fluoro-alkyl group.

of formula (I), in which R3 of formula (I), in which R3

In another preferred embodiment, the invention relates to compounds of formula (I), in which R3 represents a hydrogen atom or a C1-C3 alkyl group.

In another preferred embodiment the invention relates to compounds representing a hydrogen atom, a fluorine atom or a chlorine atom, or a group

of formula (I), wherein R3 C1-C3 alkyl.

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In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a hydrogen atom, fluorine atom or chlorine atom, or a methyl or trifluoromethyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a fluorine atom or chlorine atom, or a methyl or trifluoromethyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a chlorine atom, or a methyl or trifluoromethyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a hydrogen atom, a chlorine atom, or a methyl or trifluoromethyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a methyl or trifluoromethyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a trifluoromethyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a methyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a group selected from a hydrogen, fluorine, or chlorine atom.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a fluorine or chlorine atom.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a hydrogen atom or a fluorine atom.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a fluorine atom.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a hydrogen atom or chlorine atom.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a hydrogen atom.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 3 represents a chlorine atom.

In another embodiment, the invention relates to compounds of formula (I), in which R4 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano, C1-C3 alkyl- , C1-C3- alkoxy, halo-C1-C3 alkyl, C1-C3 fluoroalkoxy.

In another embodiment the invention relates to compounds of formula (I), in which R4 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C3- alkyl, C1-C3 alkoxy- , halo-C1-C3- alkyl, C1-C3- fluoroalkoxy.

In another embodiment the invention relates to compounds of formula (I), in which R4 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C2- alkyl, C1-C2 alkoxy- , halo-C1-C2- alkyl, C1-C2- fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R4 represents a group selected from a hydrogen, fluorine or chlorine atom.

In another embodiment, the invention relates to compounds of formula (I), in which R 4 represents a fluorine or chlorine atom.

In a preferred embodiment the invention relates to compounds of formula (I), in which R4 represents a group selected from a hydrogen atom or fluorine atom.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R4 represents a fluorine atom.

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In another embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S ( O ^ R9, -C (O) NR10R11, -P (O) (OR12) 2, -CH2OP (OR12) 2, C1-C6 alkyl-, C3-C7 cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S ( O) 2R9, -C (O) NR10R11, -P (O) (O) 2, -CH2OP (O) 2, C1-C6 alkyl-, C3-C7 cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S ( O) 2R9, -C (O) NR10R11, -P (O) (OR12) 2, -CH2OP (OR12) 2, C1-C6 alkyl-, C3-C7 cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom, cyano, -C (o) r9, -C (O) OR9, -S ( O) 2R9, -C (O) NR10R11, -P (O) (O) 2, -CH2OP (O) 2, C1-C6 alkyl-, C3-C7 cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula (I), in which R5

represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11, -

P (O) (OR12) 2, -CH2OP (OR12) 2 or C1-C3 alkyl-,

wherein said C1-C3 alkyl group is optionally substituted with a substituent, selected from -NH2, alkylamino-, dialkylamino-, or cyclic amines.

In a preferred embodiment the invention relates to compounds of formula (I), in which R5

represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11, -

P (O) (O) 2, -CH2OP (O) 2 or C1-C3 alkyl-,

wherein said C1-C3 alkyl group is optionally substituted with a substituent, selected from -NH2, alkylamino-, dialkylamino-, or cyclic amines.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O ^ R9, -C (O) NR10R11, -P (O) (OR12) 2, -CH2OP (OR12) 2, methyl.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O ^ R9, -C (O) NR10R11, -P (O) (O) 2, -CH2OP (O) 2, methyl.

In another preferred embodiment the invention relates to compounds of formula, (I), in which R5 represents a group selected from cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9

-C (O) NR10R11,

-P (O) (OR12) 2,

CH2OP (ORl2) 2, methyl.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R5

represents a group selected from cyano, -C (O) R methyl.

-C (O) OR9, -S (O) 2R9

-C (O) NR10R11, -P (O) (O) 2,

-CH2OP (O) 2

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In another preferred embodiment the invention relates to compounds of formula (I), in which R5 represents a group selected from cyano, -S (O) 2R9, -C (O) NR10R11, -P (O) (O ) 2, -CH2OP (O) 2.

In a preferred embodiment the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11.

In another preferred embodiment the invention relates to compounds of formula (I), in which R5 represents a group selected from cyano, -C (O) OR9, -C (O) NR10R11.

In another embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from cyano or -C (O) OR9.

In another embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom or a cyano group.

In another embodiment the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom or -C (O) OR9.

In another embodiment the invention relates to compounds of formula (I), in which R5 represents -C (O) OR9.

In another embodiment the invention relates to compounds of formula (I), in which R5 represents -C (O) NR10R11.

In another embodiment the invention relates to compounds of formula (I), in which R5 represents -C (O) R9.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 5 represents a cyano group.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R5 represents a group selected from a hydrogen atom or -C (O) R9.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 5 represents a hydrogen atom.

In another embodiment, the invention relates to compounds of formula (I), in which R6, R7 independently represent each other, a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1- C3-alkyl, C1-C3- alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R6 and R7 independently represent each other, a group selected from hydrogen or fluorine atom or C1-C3 alkoxy.

In a preferred embodiment the invention relates to compounds of formula (I), in which R6 and R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom .

In another embodiment, the invention relates to compounds of formula (I), in which R6 and R7 independently represent each other, a group selected from hydrogen or fluorine atom.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R6 represents hydrogen, para-fluoro, or para-chloro, where for reference the point of attachment of R2 to the rest of the molecule , and in which R7 represents a hydrogen atom.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R6 represents para-fluoro, where it refers to the point of attachment of R2 to the rest of the molecule, and in which R7 represents a hydrogen atom.

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 6 represents a fluorine atom, and in which R 7 represents a hydrogen atom.

In another embodiment, the invention relates to compounds of formula (I), in which R6 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C3- alkyl, C1-C3 alkoxy- , halo-C1-C3- alkyl, C1-C3- fluoroalkoxy.

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In a preferred embodiment the invention relates to compounds of formula representing a group selected from a hydrogen atom, fluorine atom, chlorine atom.

In another preferred embodiment, the invention relates to compounds of formula representing a hydrogen atom.

In another preferred embodiment, the invention relates to compounds of formula representing a fluorine atom.

In another preferred embodiment, the invention relates to compounds of formula representing a chlorine atom.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R6 represents hydrogen, para-fluoro, or para-chloro, where for reference the point of attachment of R2 to the rest of the molecule .

In another particularly preferred embodiment, the invention relates to compounds of formula (I), in which R6 represents para-fluoro, where it refers to the point of attachment of R2 to the rest of the molecule.

In another embodiment the invention relates to compounds of formula (I), in which R7 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C3- alkyl, C1-C3 alkoxy- , halo-C1-C3- alkyl, C1-C3- fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R7 represents a group selected from a hydrogen atom, fluorine atom, chlorine atom, C1-C2- alkyl, C1-C2 alkoxy- , halo-C1-C2- alkyl, C1-C2- fluoroalkoxy.

In a preferred embodiment the invention relates to compounds of formula representing a group selected from a hydrogen atom, fluorine atom, chlorine atom.

In another preferred embodiment, the invention relates to compounds of formula representing a fluorine atom.

In another preferred embodiment, the invention relates to compounds of formula representing a chlorine atom.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 7 represents a hydrogen atom.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a C 1 -C 6 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3- alkenyl, C2-C3- alkynyl, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl,

wherein said C3-C7-, heterocyclyl-, phenyl or heteroaryl cycloalkyl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy -, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a C 1 -C 6 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-, C3-C7- cycloalkyl, heterocyclyl-,

phenyl, heteroaryl,

wherein said C3-C7- cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy- , dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a C 1 -C 3 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3- alkenyl, C2-C3- alkynyl, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl,

wherein said C3-C7- cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3- alkyl,

(I), in which R7 (I), in which R7 (I), in which R7

(I), in which R6 (I), in which R6 (I), in which R6 (I), in which R6

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C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a C 1 -C 6 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of a halogen atom, C1-C3- alkyl, C3-C6- cycloalkyl, C3-C6- heterocyclyl, phenyl, heteroaryl,

wherein said C3-C6- cycloalkyl, C3-C6- heterocyclyl, phenyl or heteroaryl group is optionally substituted with a substituent selected from halogen.

In a preferred embodiment the invention relates to compounds of formula (I), in which R 8 represents a C 1 -C 3 alkyl group,

which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, halo-C 1 -C 3 alkyl.

In another preferred embodiment the invention relates to compounds of formula (I), in which R 8 represents a C 1 -C 3 alkyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a group selected from methyl, (2 H 3) methyl.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a methyl group.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a methyl or ethyl group.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents an ethyl group.

In another embodiment, the invention relates to compounds of formula (I), in which R8 represents a C3-C7- cycloalkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, fluoroalkoxy C1-C3-, C1-C3-alkoxy, C2-C3- alkenyl, C2-C3- alkynyl.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a cyclopentyl or cyclohexyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of fluoro, chloro, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C2 alkyl-, halo-C1-C2 alkyl-, fluoroalkoxy C1-C2-, C1-C2- alkoxy, C2-C3- alkenyl, C2-C3- alkynyl.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heterocyclyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting in halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy- , C1-C3- alkoxy, C2-C3- alkenyl, C2-C3- alkynyl.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a 4- and 7-membered heterocyclic ring, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl- , C1-C3- fluoroalkoxy, C1-C3- alkoxy, C2-C3- alkenyl, C2-C3- alkynyl.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting in halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy- , C1-C3- alkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting in halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C2 alkyl-, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy , C1-C2 alkoxy-.

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C1-C3- alkyl, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting in halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy- , C1-C3-alkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting in halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C2 alkyl-, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy , C1-C2 alkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting in halogen, dialkylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-.

In another embodiment the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 3 alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, of identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo- C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 2 alkyl group, wherein the phenyl group thereof is optionally substituted with one or two or three

substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2,

alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 2 alkyl group, wherein the phenyl group thereof is optionally substituted with one or two or three

substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2,

alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C2 alkyl-, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy, C1-C2 alkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a benzyl group, wherein the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected among the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C2 alkyl-, halo-C1-C2 alkyl-, C1-C2- fluoroalkoxy, C1-C2- alkoxy.

In another embodiment the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 3 alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, of identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-.

In another embodiment the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 3 alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, of identically or differently, selected from the group consisting of halogen, cyano, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines.

In a preferred embodiment the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 3 alkyl group, wherein the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkoxy.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 3 alkyl group, wherein the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen or C1-C3 alkoxy.

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In another preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 2 alkyl group, wherein the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen or C1-C3 alkoxy.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a phenyl-C 1 -C 2 alkyl group.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a benzyl group, wherein the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen or C1-C3 alkoxy-

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 8 represents a benzyl group.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heteroaryl-C 1 -C 3 alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, of identically or differently, selected from the group consisting of halogen, hydroxy, - NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo- C1-C3- alkyl, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heteroaryl-C 1 -C 3 alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, of identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heteroaryl-C 1 -C 2 alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, of identically or differently, selected from the group consisting of halogen, hydroxy, - NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo- C1-C3- alkyl, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a pyridyl-C 1 -C 2 alkyl group, wherein the pyridyl group is optionally substituted with one or two or three substituents, identically or different, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C2 alkyl-, halo-C1 alkyl -C2-, C1-C2 fluoroalkoxy-, C1-C2 alkoxy-.

In a preferred embodiment the invention relates to compounds of formula (I), in which R 8 represents a heteroaryl-C 1 -C 3 alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two substituents, so identical or different, selected from the group consisting of halogen, cyano, C1-C3 alkyl, halo C1-C3 alkyl, C1-C3 fluoroalkoxy, C1-C3 alkoxy.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R8

represents a pyridyl-C1-C3-alkyl group, where the pyridyl group thereof is optionally substituted with one or

two or three substituents, identically or differently, selected from the group consisting of halogen or C1-C3 alkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a pyridyl-CH 2 group, wherein the pyridyl group thereof is optionally substituted with one or two or three substituents, identically or different, selected from the group consisting of halogen, C1-C2 alkyl, halo C1-C2 alkyl, C1-C2 fluoroalkoxy, C1-C2 alkoxy.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R8

represents a pyridyl-CH2- group, where the pyridyl group thereof is optionally substituted with one or two

substituents, identically or differently, selected from the group consisting of halogen or C1-C3 alkoxy-

In another embodiment, the invention relates to compounds of formula (I), in which R8 represents a C3-C6-cycloalkyl-C1-C3-alkyl group, wherein the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-C3 alkyl-, C1-C3 alkoxy-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy.

In another embodiment the invention relates to compounds of formula (I), in which R8 represents a C3-C6-cycloalkyl-CH2- group, wherein the C3-C6- cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-C3 alkyl, C1-C3 alkoxy,

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halo-C 1 -C 3 alkyl, C 1 -C 3 fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R8 represents a cyclohexyl-CH2- or cyclopentyl-CH2- group, where the cyclohexyl or cyclopentyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from fluoro, C1-C3- alkyl, C1-C3- alkoxy, trifluoromethyl, C1-C3- fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heterocyclyl-C 1 -C 3 alkyl group, wherein the heterocyclyl group thereof is optionally substituted with one or two or three substituents, of identically or differently, selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R 8 represents a heterocyclyl-CH 2 group, where the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or different, selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl, C1-C3 fluoroalkoxy.

In another embodiment, the invention relates to compounds of formula (I), in which R9 represents a group selected from C1-C6 alkyl, halo C1-C3 alkyl, C3-C7 cycloalkyl, heterocyclyl, phenyl , benzyl or heteroaryl,

wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In another embodiment, the invention relates to compounds of formula (I), in which R9 represents a group selected from C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl-, phenyl, benzyl or heteroaryl,

wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In another embodiment the invention relates to compounds of formula (I), in which R9 represents a group selected from C1-C5- alkyl, C3-C6- cycloalkyl, heterocyclyl-, phenyl, benzyl or heteroaryl,

wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula (I), in which R 9 represents a group selected from C 1 -C 3 alkyl, halo C 1 -C 3 alkyl, or a benzyl group, wherein the phenyl group thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-.

In a preferred embodiment the invention relates to compounds of formula (I), in which R9

represents a group selected from C1-C3-, C1-C3-haloalkyl, benzyl group, wherein the phenyl group thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R9

represents a group selected from C1-C6- alkyl.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R9 represents a group selected from C1-C3-alkyl- which is optionally substituted with C1-C3 alkoxy.

In another preferred embodiment, the invention relates to compounds of formula (I), wherein R9 represents a group selected from C1-C3- alkyl, benzyl, or trifluoromethyl.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R9 represents a trifluoromethyl group.

In another embodiment the invention relates to compounds of formula (I), in which R10, R11 independently represent each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl -, phenyl, benzyl or heteroaryl,

wherein said C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1- alkyl C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, or

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R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine.

In another embodiment, the invention relates to compounds of formula (I), in which R10 and R11 independently represent each other, a group selected from hydrogen, C1-C5 alkyl-, C3-C6- cycloalkyl, heterocyclyl , phenyl or heteroaryl

wherein said C1-C5- alkyl, C3-C6- cycloalkyl, heterocyclyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl- , C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy.

In a preferred embodiment the invention relates to compounds of formula (I), in which R10 and R11 independently represent each other, a group selected from hydrogen, C1-C3- alkyl, benzyl, or R10 and R11 , together with the nitrogen atom to which they are attached, form a cyclic amine.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R10 and R11 independently represent each other, a group selected from hydrogen or C1-C2- alkyl.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R10 and R11 independently represent hydrogen or C1-C6 alkyl.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R10 and R11 represent hydrogen.

In another embodiment the invention relates to compounds of formula (I), in which R 10 represents a group selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula (I), in which R 10 represents a group selected from hydrogen, C 1 -C 3 alkyl, benzyl.

In another preferred embodiment the invention relates to compounds of formula (I), in which R 10 represents a group selected from hydrogen, C 1 -C 6 alkyl.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 10 represents a group selected from hydrogen or C 1 -C 2 alkyl.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 10 represents hydrogen.

In another embodiment the invention relates to compounds of formula (I), in which R 11 represents a group selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl,

wherein said C1-C6 alkyl-, C3-C7- cycloalkyl-, heterocyclyl-, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1 alkyl -C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-.

In a preferred embodiment the invention relates to compounds of formula (I), in which R 11 represents a group selected from hydrogen, C 1 -C 3 alkyl, benzyl.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 11 represents a group selected from hydrogen, C 1 -C 6 alkyl.

In another preferred embodiment, the invention relates to compounds of formula (I), in which R 11 represents a group selected from hydrogen or C 1 -C 2 alkyl.

In a particularly preferred embodiment, the invention relates to compounds of formula (I), in which R 11 represents hydrogen.

In another embodiment, the invention relates to compounds of formula (I), in which R12 represents a group selected from hydrogen, C1-C4 alkyl or benzyl.

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In another preferred embodiment the invention relates to compounds of formula (I), in which R12 represents a group selected from hydrogen or C1-C2 alkyl.

It should be understood that the present invention refers to any subcombination within any embodiment of the present invention of the compounds of formula (I), above.

In another preferred embodiment, the invention relates to a specific stereoisomer of the compounds of formula (I) which exhibits a lower IC50 with respect to CDK9 compared to other stereoisomers of the respective compound, determined according to the procedure 1a described below in the Materials and Procedures section.

In another preferred embodiment, the invention relates to a specific stereoisomer of compounds of formula (I) that exhibits a lower IC50 with respect to CDK9 at a high concentration of ATP compared to other stereoisomers of the respective compound, determined according to the procedure 1b described then in the Materials and Procedures section.

In another preferred embodiment, the invention relates to a specific stereoisomer of compounds of

formula (I) that exhibits greater selectivity in favor of CDK9 compared to CDK2 compared to others

stereoisomers of the respective compound, determined according to procedures 1a (CDK9) and 2 (CDK2) described below in the Materials and Procedures section.

In another preferred embodiment, the invention relates to a specific stereoisomer of compounds of

formula (I) that exhibits increased antiproliferative activity in tumor cell lines such as HeLa in

comparison to other stereoisomers of the respective compound, determined according to procedure 3 described below in the Materials and Procedures section.

In another preferred embodiment the invention relates to a specific stereoisomer of compounds of formula (I) which exhibits an aqueous solubility, for example, in water at pH 6.5, as compared to other stereoisomers of the respective compound, determined from according to procedure 4 described below in the Materials and Procedures section.

In another preferred embodiment, the invention relates to a specific stereoisomer of compounds of formula (I) that exhibits a greater apparent permeability of Caco-2 (Papp AB) through Caco-2 cell monolayers compared to other stereoisomers of the respective compound, determined according to procedure 5 described below in the Materials and Procedures section.

Even more particularly, the present invention covers compounds of formula (I) described in the Examples section of this text, below.

The combinations of two or more of the embodiments mentioned above are especially highly preferred.

In particular, the preferred subjects of the present invention are the compounds:

- (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine;

- 6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 1;

- 6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 2;

- (rac) -N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine;

- N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine, enantiomer 1;

- N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine, enantiomer 2;

- (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine;

- 6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 1;

- 6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 2;

- (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyrimidin-4-amine;

- (rac) -N- {4 - [(S-Ethylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine,

and the enantiomers, diastereomers, salts, solvates or solvate salts thereof.

The above-mentioned definitions of radicals that have been detailed in general terms or at preferred intervals also apply to final products of formula (I) and, analogously, to the starting or intermediate materials required in each case for preparation.

The invention further relates to a process for the preparation of the compounds of formula (I) according to the invention, in which N-deprotected sulfoximins of formula (I), in which R 5 represents hydrogen are reacted with suitable agents. to give N-functionalized sulfoximins of formula (I), wherein R5 is as defined for the compound of formula (I) according to the invention, but is different from hydrogen,

R

R '

HN O

\\ 0

image22

N

‘R2

R

\

N

R

OR

R '

\\ //

.S

image23

N

‘R2

(I), R5 = H

(I)

and in which process the resulting compounds are optionally, if appropriate, converted with the corresponding (i) solvents and / or (ii) bases or acids to the solvates, salts and / or solvates of the salts thereof.

The compounds of formula (6), wherein R1, R2, R3 and R4 are as defined for the compound of formula (I) 5 according to the present invention, are prepared by reacting the compounds of formula (5), wherein R1, R2, R3 and R4 are as defined for the compound of formula (I) according to the present invention,

R3

R

R '

* S

image24

N

■ R2

5

with trifluoroacetamide and 1,3-dibromo-5,5-dimethylhydantoin in the presence of an alkaline salt of ferc-butanol in a cyclic ether as a solvent, to give compounds of formula (6),

F

image25

H

2

6

10

and in which process the resulting compounds are optionally, if appropriate, converted with the corresponding (i) solvents and / or (ii) bases or acids to the solvates, salts and / or solvates of the salts thereof.

The present invention also relates to a process for the preparation of the compounds of formula (I), in which process the compounds of formula (6),

F

image26

N '

N

N

R2

6

I

H

wherein R1, R2, R3 and R4 are as defined for the compound of formula (I) according to the present invention, they are oxidized with an alkaline salt of permanganic acid in an aliphatic ketone of formula Ci-C2-C ( O) -C1-C2 alkyl- as solvent, followed, if the trifluoroacetyl group present in the compounds of formula (6) has not been removed by cleavage during the above-mentioned oxidation process, by the removal of said trifluoroacetyl group by treatment of the resulting intermediate with a suitable base in an alcoholic solvent, to give compounds of formula (I), in which R5 is hydrogen,

R

HN O \\ // .S

R1

R3

image27

‘R2

(I); R5 = H

and in which process the resulting compounds are optionally, if appropriate, converted with the corresponding (i) solvents and / or (ii) bases or acids to the solvates, salts and / or solvates of the salts thereof.

The present invention also relates to a process for the preparation of the compounds of formula (I), in which process the compounds of formula (6),

F

image28

6 h

2

wherein R1, R2, R3 and R4 are as defined for the compound of formula (I) according to the present invention, they are oxidized with an oxidant based on peroxomonosulfate in a solvent selected from an aliphatic alcohol of formula C1 alkyl -C3-OH, water and N, N-dimethylformamide, or a mixture thereof, to give the compounds of formula (I), wherein R5 is hydrogen,

image29

H

(I); R5 = H

2

and in which process the resulting compounds are optionally, if appropriate, converted with the corresponding (i) solvents and / or (ii) bases or acids to the solvates, salts and / or solvates of the salts thereof.

The present invention also relates to a process for the preparation of the compounds of formula (I), 5 in which process the compounds of formula (5), in which R1, R2, R3 and R4 are as defined for the compound of formula (I) according to the present invention,

R3

R

R '

, S

image30

N

R2

5

they are reacted with trifluoroacetamide and 1,3-dibromo-5,5-dimethylhydantoin in the presence of an alkaline salt of ferc-butanol in a cyclic ether as a solvent, to give compounds of formula (6),

F

image31

I

H

2

6

10

and in which process subsequently said compounds of formula (6) are oxidized by a suitable oxidizing agent, selected from an alkaline salt of permanganic acid and an oxidant based on peroxomonosulfate, in a solvent selected from an aliphatic ketone of formula Ci-C2- C (O) -C1-C2 alkyl, an aliphatic alcohol of the formula C1-C3-OH alkyl, water and N, N-dimethylformamide, or a mixture thereof, to give compounds of formula (I), in which R5 is hydrogen,

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H

(I); R5 = H

2

and in which process the resulting compounds are optionally, if appropriate, converted with the corresponding (i) solvents and / or (ii) bases or acids to the solvates, salts and / or solvates of the salts thereof.

The compounds according to the invention have a valuable pharmacological and pharmacokinetic spectrum of action, which could not have been predicted.

Based on the foregoing, it can be concluded that they are suitable for use as medicaments, particularly in the treatment and / or prophylaxis of various disorders, both in humans and in animals.

Within the scope of the present invention, the term "treatment" encompasses prophylaxis.

The pharmaceutical activity of the compounds according to the invention can be explained through their action as CDK9 inhibitors. Therefore, the compounds according to the general formula (I) and their enantiomers, diasteromers, salts, solvates and salts of solvates are useful as inhibitors of CDK9. In addition, the compounds according to the invention have a particularly high potency in the context of inhibition of CDK9 activity (which can be demonstrated through the reduced value of their IC50 on the CDK9 complex and the cyclin T1, which can be determined with an appropriate test).

In the context of the present invention, the value of the IC50 in relation to the CDK9 can be determined with the procedures described in the corresponding section. Preferably, this value is determined according to procedure 1a (which is an assay to determine the activity of a kinase on CDK9 / cyclin T1), which is described in the Materials and Procedures section below.

Surprisingly, it was possible to verify that the compounds according to the general formula (I) and their enantiomers, diasteromers, salts, solvates and salts of solvates can selectively inhibit CDK9, particularly in relation to other cyclin-dependent protein kinases, preferably compared to the CDK2. Accordingly, the compounds according to the general formula (I) and their pharmaceutically acceptable salts are particularly useful as selective inhibitors of CDK9.

The compounds of the present invention, which have the general formula (I), can inhibit CDK9 to a greater extent than CDK2.

In the context of the present invention, the value of the IC50 on the CDK2 can be determined with the procedures described in the corresponding section. Preferably, it is determined according to Procedure 2 ("kinase assay on CDK2 / cyclin E"), which is described in the Materials and Procedures section below.

Additionally, in comparison to the CDK9 inhibitors described in the prior art, the preferred compounds of the present invention according to the general formula (I) show a surprisingly high potency to inhibit CDK9 activity at high concentrations of ATP, which is demonstrated by its low IC50 value in the CDK9 / CycT1 kinase assay in high ATP. Therefore, these compounds have a lower probability of being displaced by competition from the ATP binding pocket of the CDK9 / CycT1 kinase due to the high intracellular concentration of ATP (R. Copeland et al., Nature Reviews Drug Discovery 2006, 5 , 730-739). According to this property, the compounds of the present invention particularly have the ability to inhibit CDK9 / CycT1 within cells for a longer period of time compared to the classic competitive kinase inhibitors of ATP. This increases the effectiveness of the antitumor cell at serious concentrations in decrease mediated by pharmacokinetic clearance of the inhibitor after dosing of a patient or an animal.

In the context of the present invention, the value of IC50 with respect to CDK9 at high concentrations of ATP can be determined by the procedures described in the procedure section below. Preferably, it is determined according to procedure 1b ("CDK9 / CycT1 kinase assay in elevated ATP") as described in

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Materials and Procedures section below.

Additionally, the preferred compounds of the present invention according to formula (I) show improved antiproliferative activity in tumor cell lines such as HeLa in comparison to the CDK9 inhibitors described in the prior art. In the context of the present invention, antiproliferative activity in tumor cell lines such as HeLa is preferably determined according to procedure 3. ("proliferation assay") described in the Materials and Procedures section below.

Additionally, the preferred compounds of the present invention according to formula (I) surprisingly show an increased solubility in water at pH 6.5 compared to the compounds described in the prior art.

In the context of the present invention the water solubility at pH 6.5 is preferably determined according to procedure 4a. ("flask solubility test with equilibrium stirring, thermodynamic solubility in water") as described in the Materials and Procedure section below.

Additionally, the preferred compounds of the present invention according to formula (I) are characterized by improved pharmacokinetic properties, such as an increased apparent permeability of Caco-2 (Papp AB) through Caco-2 cell monolayers, in comparison to the compounds known from the prior art.

Additionally, the preferred compounds of the present invention according to formula (I) are characterized by improved pharmacokinetic properties, such as a decreased output ratio (output ratio = Papp BA / Papp AB) from the basal to the apical compartment through Caco-2 cell monolayers, compared to the compounds known in the prior art.

In the context of the present invention, the apparent permeability values of Caco-2 from the basal to the apical compartment (Papp AB) or the output ratio (defined as the ratio ((Papp BA) / (Papp AB)) are preferably determined according to procedure 5. ("Caco-2 permeability test") described in the Materials and Procedures section below.

Additionally, the preferred compounds of the present invention according to formula (I) do not show significant inhibition of carbonic anhydrase-1 or -2 (IC50 values greater than 10 pM) and therefore show an improved side effect profile. in comparison to those CDK inhibitors described in the prior art that contain a sulfonamide group, which inhibits carbonic anhydrase-1 or -2. In the context of the present invention, the inhibition of carbonic anhydrase-1 and -2 is preferably determined according to procedure 6. ("carbonic anhydrase assay") described in the Materials and Procedures section below.

The present invention also describes the use of the compounds according to the invention, which have the general formula (I), in the treatment and / or prophylaxis of various disorders, preferably those disorders that are related to the activity of CDK9 or that are mediated by such activity, particularly hyperproliferative disorders, infectious diseases induced by viruses and / or cardiovascular diseases, and more preferably hyperproliferative disorders.

The compounds of the present invention can be used to inhibit the activity or expression of CDK9. Therefore, the compounds of formula (I) are expected to be valuable therapeutic agents.

The term "treat" or "treatment" has the usual meaning. Therefore, they refer, for example, to the management or care of a subject, in the context of combat, relief, reduction or improvement of a condition, a disease or a disorder, such as a carcinoma .

The term "subject" or "patient" encompasses organisms that may suffer from a proliferation-related disorder or a disorder associated with a reduced or insufficient programmed cell death (apoptosis), and also encompass those organisms that could benefit from the administration of a compound according to the invention. These organisms can be human beings or nonhuman animals. In particular, human subjects may suffer from a disorder related to cell proliferation or an associated state such as those described herein, or they may be at risk of contracting it. The term "non-human animals" encompasses vertebrates, for example, mammal animals, such as non-human primates, sheep, cows, dogs, cats and rodents, for example, mice, as well as animals. non-mammals, such as birds, particularly chickens, amphibians, reptiles, etc.

The expression "disorders related to CDK9 or mediated by it" will cover those diseases that are associated with the activity of CDK9 or those diseases in which the activity of CDK9 participates, which includes, for example, the hyperactivity of CDK9 , as well as the conditions that may be present in combination with these diseases. Examples of disorders that are related to CDK9 or that are mediated by it include disorders that are the result of increased CDK9 activity as a result of mutations in the genes that regulate CDK9 activity, such as LARP7, genes of the HEXIM1 and 2 proteins or the 7sk siRNA, the disorders that are the result of increased activity of the

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CDK9 as a consequence of the activation of CDK9 / cyclin T and RNA polymerase II by proteins of viral origin, such as HIV Tat protein or HTLV Tax protein, and disorders that are the result of increased activity of the CDK9 as a result of the activation of various mitogenic signaling pathways. The expression "hyperactivity of CDK9" refers to an enzymatic activity of CDK9 that is increased compared to that of normal non-diseased cells. It may also refer to an increased CDK9 activity that results in an undesirable proliferation of the cells or a programmed or reduced death of the cells (an apoptosis). This hyperactivity can originate in various mutations that cause a constitutive activation of CDK9.

The term "hyperproliferative disorder" encompasses those disorders in which there is an undesirable or uncontrolled proliferation of the cells, which includes those disorders in which there is a programmed or reduced death of the cells (an apoptosis). The compounds of the present invention can be used to prevent, inhibit, block, reduce, decrease or control (among other actions) the division of cells and / or to produce apoptosis. A possible procedure may comprise administering to the subject in need, which may be a mammal, such as a human being, an amount of a compound according to the present invention, or of a pharmaceutically acceptable salt, hydrate or solvate thereof. , which is effective in treating or preventing the disorder in question.

In the context of this invention, hyperproliferative disorders include, without limitation, psoriasis, keloids and other hyperplasia that affect the skin, endometriosis, skeletal disorders, disorders related to angiogenesis or proliferation of the blood vessels, pulmonary hypertension, fibrotic disorders, disorders associated with the proliferation of mesangium cells, polyps in the colon, polycystic kidney disease, benign prostatic hyperplasia (BPH) and solid tumors, such as breast cancer, respiratory tract cancer, brain cancer, cancer of the reproductive organs, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, cancer of skin, head and neck cancer, thyroid cancer, parathyroid cancer and their distant metastases. These disorders also include lymphomas, sarcomas and leukemias.

Examples of breast cancers include, without limitation, invasive duct carcinomas, invasive lob carcinomas, in situ duct carcinomas, in situ lob carcinomas, and canine breast carcinomas or of the felines.

Examples of respiratory tract cancers include, without limitation, small or non-small cell carcinomas of the lung, as well as bronchial adenomas, pleuropulmonary blastomas and mesotheliomas. Examples of brain cancers include, without limitation, gliomas in the brain stem or in the hypothalamus, cerebellar or cerebral astrocytomas, glioblastomas, medulloblastomas, ependymomas, and tumors in the neuroectoderm or pineal gland.

Tumors in the male reproductive organs include, without limitation, prostate cancer and testicular cancer. Tumors in the female reproductive organs include, without limitation, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer and sarcomas in the uterus.

Tumors in the digestive tract include, without limitation, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer , cancer of the small intestine, cancer of the salivary glands, adenocarcinomas in the anal glands and tumors in the mast cells.

Urinary tract tumors include, without limitation, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureter cancer, urethral cancer, and hereditary and sporadic papillary cancers in the kidneys.

Cancers in the eyes include, without limitation, intraocular melanomas and retinoblastomas.

Examples of liver cancers include, without limitation, hepatocellular carcinomas (carcinomas in liver cells, which may or may not have fibrolamellar variants), cholangiocarcinomas (which are carcinomas in the bile ducts of the liver) and mixed hepatocellular cholangiocarcinomas. .

Skin cancers include, without limitation, squamous cell carcinomas, Kaposi sarcomas, malignant melanomas, skin cancers that affect Merkel cells, skin cancers other than melanomas, and tumors in the mast cells

Head and neck cancers include, without limitation, larynx cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip and oral cavity cancer, cancers that affect squamous cells and oral melanomas.

Lymphomas include, without limitation, AIDS-related lymphomas, non-Hodgkin lymphomas, cutaneous lymphomas that affect T cells, Burkitt lymphomas, Hodgkin's disease, and lymphomas in the central nervous system.

Sarcomas include, without limitation, soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas, rhabdomyosarcomas, malignant histiocytosis, fibrosarcomas, hemangiosarcomas, hemangiopericytomas and leiomyosarcomas.

Leukemias include, without limitation, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and leukemia that affects hair cells.

With the compounds and methods of the present invention, it is possible to treat certain fibrotic disorders related to proliferation, that is, certain disorders that are characterized by the formation of

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Abnormal extracellular matrices, including pulmonary fibrosis, atherosclerosis, restenosis, liver cirrhosis and disorders associated with the proliferation of mesangium cells, which include kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, syndromes associated with thrombotic microangiopathy, transplant rejection and glomerulopathies.

Other conditions in humans or other mammals that can be treated with the compounds of the present invention include the development of tumors, retinopathy, encompassing diabetic retinopathy, ischemic retinal vein occlusion, retinopathy of the prematurity and age-related macular degeneration, rheumatic arthritis, psoriasis and bulbous disorders associated with the formation of subepidermal blisters, which includes bulbous pemphigoid, erythema multiforme and dermatitis herpetiformis.

The compounds of the present invention can also be used to prevent or treat diseases in the airways or lungs, diseases in the gastrointestinal tract or diseases in the bladder or bile ducts.

The disorders mentioned above have been well characterized in humans, but they also occur with a similar etiology in other animals, including other mammals, and it is possible to treat them with the pharmaceutical compositions of the present invention.

The compounds according to the general formula (I) can also be useful for preventing and / or treating cardiovascular diseases such as cardiac hypertrophy, congenital heart disease affecting adults, aneurysms, stable angina, unstable angina, angina pectoris, angioneurotic edema, stenosis in the aortic valve, aortic aneurysms, arrhythmias, arrhythmogenic dysplasia in the right ventricle, arteriosclerosis, arteriovenous deformations, atrial fibrillation, Behcet syndrome, bradycardia, cardiac occlusions, cardiomyalgia, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, carotid stenosis, hemorrhages in the brain, Churg-Strauss syndrome, diabetes, Ebstein's anomaly, Eisenmenger complex, embolisms due to cholesterol, endocarditis of bacterial origin, fibromuscular dysplasia, birth defects in the heart n, heart disease, congestive heart failure, heart valve diseases, heart attacks, epidural hematomas, subdural hematomas, Hippel-Lindau disease, hyperemia, hypertension, pulmonary hypertension, hypertrophic developments, hypertrophy of the left ventricle, hypoplasic syndrome in the left ventricle of the heart, hypotension, intermittent claudication, ischemic heart disease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, prolapse of mitral valve with a long QT interval, Moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vessel diseases, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud's disease, Sneddon syndrome, stenosis, upper vena cava syndrome, X syndrome, tachycardia, Takayasu arteritis, hereditary hemorrhage telangiectasia, telangiectasis, temporal arteritis, Tetralogy of Fallot, thromboangiitis obliterans, thrombosis, thromboembolism, atresia in the tricuspid valve, varicose veins in varicose veins veins, diseases in the vessels, vasculitis, vasospasm, ventricular fibrillation, Williams syndrome, leg ulcers, thrombosis in deep veins or Wolff-Parkinson-White syndrome.

Cardiac hypertrophy, congenital heart disease affecting adults, aneurysms, angina, angina pectoris, arrhythmias, cardiovascular diseases, cardiomyopathy, congestive heart failure, myocardial infarction, pulmonary hypertension is preferred , hypertrophic developments, restenosis, stenosis, thrombosis or arteriosclerosis.

Another object of the present invention is the use of the compounds of general formula (I) in accordance with the invention for the treatment and / or prophylaxis of disorders, in particular of the disorders mentioned above.

Another object of the present invention is the use of the compounds of general formula (I) according to the invention for the treatment and / or prophylaxis of disorders, in particular lung carcinomas, especially non-small cell lung carcinomas, carcinomas of prostate, especially hormone independent human prostate carcinomas, cervical carcinomas, which includes multifarm-resistant human cervical carcinomas, colorectal carcinomas, melanomas, ovarian carcinomas or leukemia, especially acute myeloid leukemia.

A further object of the present invention is the use of the compounds according to the invention in the manufacture of a method for treating and / or preventing the disorders mentioned above.

A preferred object of the present invention is the use of the compounds according to the invention in the manufacture of a medicament for the treatment and / or prophylaxis of lung carcinomas, especially non-small cell lung carcinomas, prostate carcinomas, especially Human prostate carcinomas independent of hormones, cervical carcinomas, including multi-drug resistant cervical carcinomas, colorectal carcinomas, melanomas, ovarian carcinomas or leukemias, especially acute myeloid leukemia.

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Another aspect of the present invention relates to pharmaceutical combinations comprising a compound according to the invention, which has the general formula (I), together with at least one or more additional active ingredients.

As used herein, the term "pharmaceutical combination" refers to a combination of at least one compound according to the invention, which presents the general formula (I) and which fulfills the function of an active principle, with the less another active ingredient, with additional ingredients, vehicles, diluents and / or solvents or without them.

Another aspect of the present invention relates to pharmaceutical compositions comprising a compound according to the invention, which has the general formula (I), in combination with an inert, non-toxic and pharmaceutically acceptable adjuvant.

As used herein, the term "pharmaceutical composition" refers to a galenic formulation comprising at least one agent with pharmaceutical activity combined with at least one additional ingredient, a vehicle, a diluent and / or a solvent.

Another aspect of the present invention relates to the use of pharmaceutical combinations and / or pharmaceutical compositions in accordance with the invention in the treatment and / or prophylaxis of various disorders, particularly those disorders mentioned above.

The compounds of formula (I) may be administered in the form of individual pharmaceutical agents or in combination with one or more additional therapeutic agents, such that the combination does not cause unacceptable side effects. This pharmaceutical combination may comprise a single dosage form with a compound of formula (I) and one or more additional therapeutic agents. Alternatively, the compound of formula (I) and each additional therapeutic agent can be found in its own dosage form. For example, the compound of formula (I) and the additional therapeutic agent can be administered to the patient in a single oral dosage form, which may be a tablet or a capsule. Alternatively, each agent can be administered in its own dosage form.

When separate dosage forms are used, the compound of formula (I) and the one or more additional therapeutic agents may be administered in an essentially simultaneous manner (ie, at the same time) or at separate times (e.g., consecutively) .

In particular, the compounds of the present invention can be used in single or separate combinations with other antitumor agents, which can be alkylating agents, antimetabolites, antitumor agents of plant origin, agents that can be used in hormonal therapies, topoisomerase inhibitors, derivatives of camptothecin, kinase inhibitors, targeted drugs, antibodies, interferons, biological response modifiers, antiangiogenic compounds or other antitumor drugs. In relation to the foregoing, a non-limiting list of various examples of secondary agents that may be used in combination with the compounds of the present invention is provided below:

• Alkylating agents include, without limitation, nitrogen mustard N-oxides, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temozolomide, altretamine, apaziquone, brostalicin, bendamustine, carmustine , estramustine, fotemustine, glufosfamide, mafosfamide, bendamustine and mitolactol; alkylating compounds coordinated with platinum include, without limitation, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin.

• Antimetabolites include, without limitation, methotrexate, 6-mercaptopurine ribosides, mercaptopurine, 5-fluorouracil, which can be used alone or in combination with leucovorin, tegafur, doxifluridine, carmofur, cytarabine, octophosphate of cytarabine, enocitabine, gemcitabine, fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethinylcitidine, cytosine arabinoside, hydroxyurea, melphalan, nelarabine nolatrexed, ocphosphite, premetrexed disodium, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine and vinorelbine.

• Agents that can be used in hormonal therapies include, without limitation, exemestane, lupron, anastrozole, doxercalciferol, fadrozole, formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors, 17- inhibitors. alpha hydroxylase / 17.20 lyase, such as abiraterone acetate, 5-alpha reductase inhibitors, such as finasteride and epristeride, antiestrogens, such as tamoxifen citrate and fulvestrant, trelstar, toremifene , raloxifene, lasofoxifene, letrozole, antiandrogens, such as bicalutamide, flutamide, mifepristone, nilutamide and casedex, antiprogesterones and combinations thereof.

• Antitumor substances of plant origin include, for example, mitosis inhibitors, for example, epothilones, such as sagopilone, ixabepilone or epothilone B, vinblastine, vinflunine, docetaxel and paclitaxel.

• Topoisomerase inhibiting cytotoxic agents include, without limitation, aclarubicin, doxorubicin, amonafide, belotecane, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecane, irinotecan, topotecan, edotecaine, epimbicin, etoposide, exatecane, gimatecan, lurtotecan, mitoxantrone, pyramycin, pixantrone, rubitecan, sobuzoxane,

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Tafluposide and combinations of these.

• Agents that act on the immune system include interferons, such as interferon alfa, interferon alfa-2a, interferon alfa-2b, interferon beta, interferon gamma-1a and interferon gamma-n1, and other agents to boost the immune system, such as L19-IL2 and other derivatives of IL2, filgrastim, lentinan, sizophilane, TeraCys, ubenimex, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin , gemtuzumab, ozogamycin, ibritumomab, imiquimod, lenograstim, the vaccine against melanoma of Corixa, the vaccine against melanoma of Merial, molgramostim, sargramostim, tasonermine, tecleuquine, thimalasin, tositumomab, vimlizine, epratuzumab, mitumomab, oregovomab, pemtumomab and Provenge.

• The modifiers of the biological responses include those agents with which the defense mechanisms of living organisms can be modified and those agents with which biological parameters such as survival, growth or differentiation of the cells that constitute the tissues can be modified, in which case they can confer antitumor activity. These agents include, for example, krestine, lentinano, sizofirano, picibanil, ProMune and ubenimex.

• Anti-angiogenic compounds include, without limitation, acitretin, aflibercept, angiostatin, aplidine, seating, axitinib, recentin, bevacizumab, brivanib, alaninat, cilengtide, combretastatin, DAST, endostatin, fenretinide, halofuginone, pazopanib, ranibizumab, rebimastat, removab, revlimid, sorafenib, vatalanib, squalamin, sunitinib, telatinib, thalidomide, ukraine and vitaxin.

Antibodies include, without limitation, trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, catumaxomab, atacicept, oregovomab and alemtuzumab.

VEGF inhibitors, such as, for example, sorafenib, DAST, bevacizumab, sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib, alaninate, vatalanib, pazopanib, ranibizumab and Palladia . EGFR (HER1) inhibitors such as, for example, cetuximab, panitumumab, vectibix, gefitinib, erlotinib and Zactima.

HER2 inhibitors such as, for example, lapatinib, tratuzumab and pertuzumab.

MTOR inhibitors such as, for example, temsirolimus, sirolimus, rapamycin and everolimus. c-Met inhibitors; PI3K and AKT inhibitors;

CDK inhibitors, such as roscovitine and flavopyridol.

Inhibitors of spindles in spindle assembly and targeted antifungal agents include, for example, PLK inhibitors, Aurora inhibitors (eg, hesperadin), kinase inhibitors found in checkpoints and KSP inhibitors.

HDAC inhibitors such as, for example, panobinostat, vorinostat, MS275, belinostat and LBH589. HSP90 and HSP70 inhibitors;

proteasome inhibitors, such as bortezomib and carfilzomib.

Serine and threonine kinase inhibitors include, for example, MEK inhibitors, (such as RDEA 119), and Raf inhibitors, such as sorafenib.

Farnesyl transferase inhibitors include, for example, tipifarnib.

Tyrosine kinase inhibitors include, for example, dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate, brivanib , alaninate, pazopanib, ranibizumab, vatalanib, cetuximab, panitumumab, vectibix, gefitinib, erlotinib, lapatinib, tratuzumab, pertuzumab, c-Kit inhibitors, Palladia and masitinib.

• Vitamin D receptor agonists.

• Bcl-2 protein inhibitors such as, for example, obatoclax, sodium oblimersen and gosipol.

• The antagonists of the set of receptors that participate in differentiation number 20 include, for example, rituximab.

• Ribonucleotide reductase inhibitors include, for example, gemcitabine.

• Ligand receptor agonists that induce apoptosis 1 include, for example, mapatumumab.

• 5-Hydroxytryptamine receptor antagonists include, for example, rEV598, xaliprode, palonosetrone hydrochloride, granisetron, zindole and AB-1001.

• Integrin inhibitors include alpha 5-beta 1 integrin inhibitors, such as E7820, JSM 6425, volociximab, and endostatin.

• Androgen receptor antagonists include, for example, nandrolone decanoate, fluoxymesterone, Android, Prost-aid, andromustine, bicalutamide, flutamide, apo-cyproterone, apoflutamide, chlormadinone acetate Androcur, Tabi, cyproterone acetate and nilutamide.

• Aromatase inhibitors include, for example, anastrozole, letrozole, testolactone, exemestane, aminoglutethimide and formestane.

• Various matrix metalloproteinase inhibitors can also be used.

• Other anticancer agents include, for example, alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, bosentan, calcitriol, exisulind, fotemustine, ibandronic acid, miltefosine, mitoxantrone, I-asparagine , procarbazine, dacarbazine, hydroxycarbamide, pegaspargasa, pentostatin, tazarotene, velcade, gallium nitrate, canfosfamide, darinaparsine and tretinoin.

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The compounds of the present invention can also be combined with radiation therapy and / or with various surgical interventions.

Generally, the use of cytotoxic and / or cytostatic agents in combination with the compounds or compositions of the present invention will achieve.

(1) Obtaining superior efficacy in the context of the reduction of tumor growth, or even the removal of tumors, compared to the result that could be obtained with the administration of any of the agents separately.

(2) The possibility of administering smaller amounts of chemotherapeutic agents.

(3) The implementation of a chemotherapeutic treatment that can be well tolerated by the patient, with fewer pharmacological complications than those that could be obtained with any of the agents separately or with any other combination.

(4) Obtaining a broader spectrum of cancer treatment in mammals, especially in humans.

(5) Obtaining a higher frequency of response among treated patients.

(6) Obtaining a longer survival among treated patients, compared to conventional chemotherapeutic treatments.

(7) The delay in the progress of tumors.

(8) Obtaining efficacy and tolerability at least as good as those that could be obtained with any of the agents separately, or in comparison with any other possible combination.

In addition, the compounds of formula (I) can be used, alone or in compositions, in research, in diagnosis, as reference tools in various analyzes or for similar purposes well known in the art.

The compounds according to the invention may have a systematic and / or local action. In this context, it is possible to administer them by an appropriate route, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, otic or through the conjunctiva, or in the form of implants or stents.

For these routes of administration, the compounds according to the invention can be administered in suitable application forms.

When an oral administration is used, administration forms such as those described in the technical background can be employed, with which the compounds according to the invention can be administered rapidly, directly and / or in modified forms. In this context, the compounds according to the invention can be administered in crystalline, amorphous and / or dissolved forms, for example, in the form of tablets, which can rapidly decompose in the oral cavity (where the tablets may be coated or not, and where the coatings can be enteric coatings, with which a delayed administration can be made, or they can be insoluble coatings, with which the release of the compounds according to the invention can be controlled, films, which can be combined with wafers or lyophilized , capsules (which can be hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

A parenteral administration can be used without absorption steps (in which case parenteral administration encompasses intravenous, intraarterial, intracardiac, intraspinal and intralumbar administration) or with absorption steps (in which case parenteral administration encompasses intramuscular, subcutaneous, intracutaneous administration , percutaneous and intraperitoneal). Appropriate administration forms for parenteral administration include injectable preparations and infusions in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders, among others.

Other appropriate forms of administration include, for example, inhalers and nebulizers, which can be used in administration by inhalation, drops, solutions and sprays, which can be used in nasal administration, tablets, films, wafers and capsules, which can be used in lingual, sublingual or buccal administration, suppositories, which can be used in rectal administration, preparations that can be administered ocularly or otically, capsules that can be administered vaginally, aqueous suspensions, for example, lotions or agitated mixtures, lipophilic suspensions, ointments, creams, transdermal therapeutic systems, including casts, milk, pastes, foams, powders , implants and intraluminal devices.

The compounds according to the invention can be used in the administration forms mentioned above. To prepare them, it is possible to mix them with inert, non-toxic and pharmaceutically acceptable adjuvants. These adjuvants include, among others, vehicles (for example, microcrystalline cellulose, lactose or mannitol), solvents (for example, liquid polyethylene glycols), emulsifiers, dispersants or wetting agents (for example, dodecyl sodium sulfate or polyoxysorbitan oleate), binders (for example, polyvinylpyrrolidone), synthetic or natural polymers (for example, albumin), stabilizers (for example, antioxidants, such as ascorbic acid), dyes (for example, inorganic pigments, such as iron oxides) and masking agents

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The taste and / or aroma.

The present invention also provides medicaments comprising at least one compound according to the invention, usually in combination with one or more inert, non-toxic and pharmaceutically acceptable adjuvants, and their use in the applications listed above.

When the compounds of the present invention are to be administered in the form of drugs in humans or animals, it is possible to use them alone or in the form of pharmaceutical compositions, which may contain, for example, between 0.1% and 99.5% (more preferably between 0.5% and 90%) of the active ingredient, which may be combined with one or more inert, non-toxic and pharmaceutically acceptable adjuvants.

Regardless of the route of administration selected, the compounds according to the invention, which can present the general formula (I), and / or the pharmaceutical compositions according to the present invention can be formulated in pharmaceutically acceptable dosage forms, for which procedures known to those skilled in the art can be used.

The dosage levels and the duration of administration of the active ingredients in the pharmaceutical compositions according to the invention may be modified in order to administer an amount that is appropriate to obtain the desired therapeutic response in the patient to be treated, and so that additionally no toxic effects occur.

Materials and Procedures

The percentage values provided in the tests and the examples below are weight percentages, unless otherwise indicated. Also, the parts are parts by weight. The proportions between the solvents, the proportions of the dilutions and the data related to the concentration of the solutions that only comprise liquids are based on the volume.

The examples were tested in specific biological tests, on one or more occasions. When they were subjected to more than one analysis, the data reported are the average values or the median values, in which

• The average value, which is also known as the arithmetic mean, is the sum of the values obtained, divided by the amount of analysis performed.

• The median value is the value of the medium in the group of values sorted in ascending or descending order. If the amount of values in the data set is odd, the median is the value of the medium. If the amount of values in the data set is even, the median is the arithmetic mean of the two values of the medium.

The examples were synthesized on one or more occasions. When synthesized more than once, the biological test data are the average values or the median values, which were calculated based on the data obtained when each batch of compounds was analyzed.

The pharmacological properties of the compounds can be determined in vitro according to the assays and procedures described below.

1st. Kinase assay with CDK9 / cyclin T1:

The CDK9 / cyclin T1 inhibition activity of the compounds of the present invention was determined using the TR-FRET-based assay described below.

A human CDK9 and a cyclin T1 complete and labeled with His were acquired, which had been expressed in insect cells and purified by means of a chromatography of affinity with Ni-NTA, in Invitrogen (cat. # PV4131). As a substrate for the reaction with the kinase, biotinylated biotinylated peptide-Ttds-YISPLKSPYKISEG (with the C-shaped amide) was used, which can be purchased, for example, from the JERINI Peptide Technologies company (Berlin, Germany).

In the test, with a pipette 50 nl of a 100-fold concentrated solution of the test compound in DMSO was placed in a microtiter plate of 384 cavities with reduced volumes (from Greiner Bio-One, Frickenhausen, Germany), where they were also added 2 pl of a solution of the complex of CDK9 and cyclin T1 in an aqueous buffer for the assay (comprising 50 mM Tris / HCl, pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, sodium orthovanadate 0, 1 mM and 0.01% (volume by volume) of Nonidet-P40, from Sigma). The mixture was incubated at 22 ° C for 15 minutes to allow preliminary binding to occur between the test compounds and the enzyme, before the start of the reaction with the kinase. Then, the reaction with the kinase was started by adding 3 pl of an adenosine triphosphate solution (ATP 16.7 pM, which in the test volume, 5 pl, represented a concentration of 10 pM) and the substrate (1.25 pM, which in the test volume, 5 pl, represents a concentration of 0.75 pM) in the test buffer. The resulting mixture was incubated at a temperature of 22 ° C for a period of 25 minutes. The concentration of the CDK9 complex and the cyclin T1 was adjusted based on the activity of the enzyme batch, and was appropriate to maintain a linear interval in the assay. Concentrations

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Typical were approximately 1 pg / ml. The reaction was stopped by adding 5 pi of a solution of the termination reagents for TR-FRET (streptavidin-XL665 0.2 pM, from Cisbio Bioassays, Codolet, France, an anti-RB antibody (pSer807 / pSer811) 1 nM, of BD Pharmingen, No. 558389, and a mouse anti-IgG antibody labeled with LANCE EU-W1024 1.2 nM, from Perkin-Elmer, product No. AD0077) in an aqueous solution of EDTA (with 100 mM EDTA and 0.2% (w / v) bovine serum albumin in HEPES / 100 mM NaOH, pH 7.0).

The resulting mixture was incubated at 22 ° C for 1 h to allow a complex to form with the phosphorylated biotinylated peptide and termination reagents. Then, the amount of the phosphorylated substrate was determined by measuring the resonance energy transfer from chelated with Eu to streptavidin-XL. Fluorescence emissions at 620 nm and 665 nm were measured after applying an excitation at 350 nm in a TR-FRET reader, for example, in a Rubystar reader (from BMG Labtechnologies, Offenburg, Germany) or in a Viewlux reader ( from Perkin-Elmer). The ratio between the emissions at 665 nm and 622 nm was taken as the measure of the amount of the phosphorylated substrate. The data were subjected to a normalization based on the reaction that comprised the enzymes, but not the inhibitors, which represented a 0% inhibition, and on the basis of the reaction that comprised all the other components, but not the enzyme, which represents a 100% inhibition. Usually, the test compounds were analyzed on the same microtiter plate, in 11 different concentrations in the range of 20 pM to 0.1 nM (20 pM, 5.9 pM, 1.7 pM, 0.51 pM, 0.15 pM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM; the dilution series was prepared separately, before testing, with solutions 100 times concentrated in DMSO, through serial dilutions of 1 in 3.4), with each concentration in duplicate. The IC50 values were determined through a 4 parameter setting using local software.

1 B. Kinase assay with CDK9 / CycT1 in elevated ATP

The CDK9 / CycT1 inhibitory activity of the compounds of the present invention was quantified at a high concentration of ATP after enzyme pre-incubation and test compounds using the TR-FRET assay for CDK9 / CycT1 as described in the following paragraphs.

His full-length recombinant human CDK9 and CycT1 were purchased, expressed in insect cells and purified by Ni-NTA affinity chromatography, at Invitrogen (Cat. No PV4131). As a substrate for the kinase reaction, biotinylated biotinylated-Ttds-YISPLKSPYKISEG peptide (C-terminal amide form) was used, which was acquired, for example, from the JERINI peptide technologies company (Berlin, Germany).

For the test, 50 nl of a 100-fold concentrated solution of the test compound in DMSO was loaded with a pipette into a microtiter plate of 384 black small volume cavities (Greiner Bio-One, Frickenhausen, Germany), 2 pl of one CDK9 / CycT1 solution in aqueous test buffer solution [50 mM Tris / HCl pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 1.0 mM sodium ortho vanadate, 0.01% Nonidet-P40 ( volume by volume) (Sigma)] and the mixture was incubated for 15 minutes at 22 ° C to allow preliminary binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was initiated by the addition of 3 pl of an adenosine tri-phosphate solution (ATP, 3.3 mM, which in the test volume, 5 pl, represented a concentration of 2 mM) and substrate (1.67 pM, which in the test volume, 5 pl, represents a concentration of 1 pM) in the test buffer solution and the resulting mixture was incubated for a reaction time of 25 minutes at 22 ° C. The concentration of CDK9 / CycT1 was adjusted depending on the activity of the enzyme batch and was chosen appropriate to have the assay in the linear range, the typical concentrations were in the range of 0.5 pg / ml. The reaction was stopped by the addition of 5 pl of a solution of TR-FRET detection reagents (streptavidin-XL665 0.2 pM [Cisbio Bioassays, Codolet, France] and anti-RB antibody (pSer807 / pSer811) 1 nM of BD Pharmingen [No. 558389] and 1.2 nM LaNcE EU-W1024-labeled mouse anti-IgG antibody [Perkin-Elmer, product no. AD0077]) in an aqueous solution of EDTA (100 mM EDTA, serine albumin 0.2% bovine (volume weight) in 100 mM HEPES / NaOH pH 7.0).

The resulting mixture was incubated 1 hour at 22 ° C to allow complex formation between the phosphorylated biotinylated peptide and the detection reagents. Subsequently, the amount of phosphorylated substrate was evaluated by measuring the resonance energy transfer of Chelated with Eu to streptavidin-XL. Therefore, fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in an HTRF reader, for example, a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer) . The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. Data were normalized (enzymatic reaction without inhibitor = 0% inhibition, all other components of the assay, but without enzyme = 100% inhibition). Test compounds are usually tested on the same microtiter plate in 11 different concentrations in the range between 20 pM and 0.1 nM (20 pM, 5.9 pM, 1.7 pM, 0.51 pM, 0.15 pM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM, series of dilutions prepared separately before testing at the level of solutions 100 times concentrated in DMSO by serial dilutions of 1: 3.4) in duplicate values for each concentration and the IC50 values were calculated by adjusting 4 parameters using a proprietary computer program.

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2nd. Kinase assay with CDK2 / cyclin E

The inhibition activity of the CDK2 / cyclin E of the compounds of the present invention was determined using the TR-FRET-based assay described in the following paragraphs.

Recombinant fusion proteins comprising human GST and CDK2 and human GST and cyclin E were acquired, which had been expressed in insect cells (Sf9) and purified by means of an affinity chromatography with glutathione and sepharose, in ProQinase GmbH (Freiburg, Germany). As a substrate for the reaction with the kinase, the biotinylated biotinylated peptide-Ttds-YISPLKSPYKISEG (with the C-shaped amide) was used, which can be purchased, for example, from the JERINI Peptide Technologies company (Berlin, Germany).

For the test, with a pipette 50 nl of a 100-fold concentrated solution of the test compound in DMSO was placed in a microtiter plate of 384 cavities with reduced volumes (from Greiner Bio-One, Frickenhausen, Germany), where they were also added 2 pl of a solution of the CDK2 and cyclin E complex in an aqueous buffer for the assay (comprising 50 mM Tris / HCl, pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 0 sodium orthovanadate, 1 mM and 0.01% (volume by volume) of Nonidet-P40, from Sigma). The mixture was incubated at 22 ° C for 15 minutes to allow preliminary binding to occur between the test compounds and the enzyme, before the start of the reaction with the kinase. Then, the reaction with the kinase was started by adding 3 pl of an adenosine triphosphate solution (ATp 16.7 pM, which in the test volume, 5 pl, represents a concentration of 10 pM) and the substrate (1, 25 pM, which in the volume of the test, 5 pl, represents a concentration of 0.75 pM) in the test buffer. The resulting mixture was incubated at a temperature of 22 ° C for a period of 25 minutes. The concentration of the CDK2 complex and cyclin E was adjusted based on the activity of the enzyme batch, and was appropriate to maintain a linear interval in the assay. Typical concentrations were approximately 130 ng / ml. The reaction was stopped by adding 5 pl of a solution of the termination reagents for TR-FRET (streptavidin-XL665 0.2 pM, from Cisbio Bioassays, Codolet, France, an anti-RB antibody (pSer807 / pSer811) 1 nM, of BD Pharmingen, No. 558389, and a mouse anti-IgG antibody labeled with LANCE EU-W1024 1.2 nM, from Perkin-Elmer, product No. AD0077) in an aqueous solution of EDTA (with 100 mM EDTA and 0.2% (w / v) bovine serum albumin in HEPES / 100 mM NaOH, pH 7.0).

The resulting mixture was incubated at 22 ° C for 1 hour to allow a complex to form with the phosphorylated biotinylated peptide and termination reagents. Then, the amount of the phosphorylated substrate was determined by measuring the resonance energy transfer from chelated with Eu to streptavidin-XL. Fluorescence emissions at 620 nm and 665 nm were measured after applying an excitation at 350 nm in a TR-FRET reader, for example, in a Rubystar reader (from BMG Labtechnologies, Offenburg, Germany) or in a Viewlux reader ( from Perkin-Elmer). The ratio between the emissions at 665 nm and 622 nm was taken as the measure of the amount of the phosphorylated substrate. The data were subjected to a normalization based on the reaction that comprised the enzymes, but not the inhibitors, which represented a 0% inhibition, and on the basis of the reaction that comprised all the other components, but not the enzyme, which represents a 100% inhibition. Usually, the test compounds were analyzed on the same microtiter plate, in 11 different concentrations in the range of 20 pM to 0.1 nM (20 pM, 5.9 pM, 1.7 pM, 0.51 pM, 0.15 pM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM; the dilution series was prepared separately, before testing, with solutions 100 times concentrated in DMSO, through serial dilutions of 1 in 3.4), with each concentration in duplicate. The IC50 values were determined through a 4 parameter setting using local software.

2b Kinase assay with CDK2 / CycE in elevated ATP:

The CDK2 / CycE inhibitory activity of compounds of the present invention in 2 mM adenosine tri-phosphate (ATP) was quantified using the TR-FRET assay for CDK2 / CycE (TR-FRET = fluorescence energy transfer with temporal resolution ) as described in the following paragraphs.

Recombinant fusion proteins of human GST and CDK2 and human GST and CycE, expressed in insect cells (Sf9) and purified by glutathione sepharose affinity chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). As a substrate for the kinase reaction, the biotinylated biotin-Ttds-YISPLKSPYKISEG peptide (terminal C-shaped amide) was used, which could be purchased, for example, from the JERINI peptide technologies company (Berlin, Germany).

For the test, with a pipette 50 nl of a 100-fold concentrated solution of the test compound in DMSO was placed in a microtiter plate of 384 cavities with reduced volumes (from Greiner Bio-One, Frickenhausen, Germany), where they were also added 2 pl of a solution of CDK2 / CycE in an aqueous buffer for the assay (comprising 50 mM Tris / HCl, pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 0.1 mM sodium orthovanadate and 0, 01% (volume by volume) of Nonidet-P40, from Sigma) and the mixture was incubated at 22 ° C for 15 minutes to allow preliminary binding between the test compounds and the enzyme to occur, before the start of the reaction with the kinase Then, the reaction with the kinase was started by adding 3 pl of an ATP solution (3.33 mM, which in the test volume, 5 pl, represented a concentration of 2 pM) and the substrate (1.25 pM, which in the test volume, 5 pl, I represent a concentration of 0.75 pM) in the test buffer. The resulting mixture was incubated at a temperature of 22 ° C for a period of 25 minutes. The concentration of the complex

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of CDK2 / CycE was adjusted based on the activity of the enzyme batch, and was appropriate to maintain a linear interval in the assay. Typical concentrations were in the range of approximately 15 ng / ml. The reaction was stopped by adding 5 pl of a termination reagent solution for TR-FRET [streptavidin-XL665 0.2 pM, from Cisbio Bioassays, Codolet, France], an anti-RB antibody (pSer807 / pSer811) 1 nM , from BD Pharmingen, No. 558389, and a 1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody (Perkin-Elmer, product No. AD0077), alternatively the mouse anti-IgG antibody can be used labeled with Terbio-Crybio Bioassays]) in an aqueous solution of EDTA (100 mM EDTA and 0.2% (volume weight) of bovine serum albumin in 100 mM HEPES / NaOH, pH 7.0).

The resulting mixture was incubated at 22 ° C for 1 hour to allow a complex to form with the phosphorylated biotinylated peptide and detection reagents. Then, the amount of the phosphorylated substrate was determined by measuring the resonance energy transfer from chelated with Eu to streptavidin-XL. Fluorescence emissions at 620 nm and 665 nm were measured after applying an excitation at 350 nm in a TR-FRET reader, for example, in a Rubystar reader (from BMG Labtechnologies, Offenburg, Germany) or in a Viewlux reader ( from Perkin-Elmer). The ratio between the emissions at 665 nm and 622 nm was taken as the measure of the amount of the phosphorylated substrate. Data were normalized (enzymatic reaction without inhibitor = 0% inhibition, all other components of the assay, but without enzyme = 100% inhibition). Usually, the test compounds were analyzed on the same microtiter plate, in 11 different concentrations in the range of 20 pM to 0.1 nM (20 pM, 5.9 pM, 1.7 pM, 0.51 pM, 0.15 pM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM; the dilution series was prepared separately, before testing, with solutions 100 times concentrated in DMSO, through serial dilutions of 1 in 3.4), with each concentration in duplicate. The IC50 values were determined through a 4 parameter setting using a proprietary computer program.

3. Proliferation test

Cultured tumor cells were plated (HeLa, human cervical tumor cells, ATCC CCL-2; NCI-H460, non-small cell lung carcinoma cells, ATCC HTB-177; A2780, human ovarian carcinoma cells, ECACC n. 93112519; DU 145, hormone independent human prostate carcinoma cells, ATCC HTB-81; HeLa-MaTu-ADR, multi-drug resistant cervical carcinoma cells, EPO-GmbH Berlfn; Caco-2, human colorectal carcinoma cells , ATCC HTB-37; B16F10, mouse melanoma cells, ATCC CRL-6475) at a density of 5,000 cells per cavity (DU145, HeLa-MaTu-ADR), 3,000 cells per cavity (NCI-H460, HeLa), 2,500 cells per cavity (A2780), 1,500 cells per cavity (Caco-2), or 1,000 cells per cavity (B16F10) in a 96-well microtiter plate in 200 pl of their respective growth media supplemented with 10% bovine fetal serum . After 24 hours, the cells of one plate (the 0% equivalent plate) were colored with crystalline violet (see description below), while the medium of the other plates was changed to a fresh culture medium (200 pl ), to which the test substances were added in various concentrations (0 pM and a range between 0.001 and 10 pM; the final concentration of the solvent, dimethyl sulfoxide, was 0.5%). The cells were incubated for 4 days in the presence of the test substances. The proliferation of the cells was determined by coloring them with crystalline violet, for which the cells were fixed by adding 20 pl / measuring point of a solution of 11% glutaric aldehyde, at room temperature for 15 minutes. After subjecting the fixed cells to three wash cycles with water, the plates were dried at room temperature. The cells were colored by adding 100 pl / measuring point of a 0.1% crystalline violet solution (with a pH of 3.0). After subjecting the colored cells to three wash cycles with water, the plates were dried at room temperature. The dye was dissolved by adding 100 pl / measuring point of a 10% acetic acid solution. The extinction was determined by photometric means, with a wavelength of 595 nm. The change in the amount of cells, which was expressed as a percentage, was calculated by subjecting the measured values to a normalization based on the extinction in the control plate equivalent to 0% and the extinction in the untreated cells (0 pM) , equivalent to 100%. The IC50 values (50% inhibitory concentration of the maximum effect) were determined by means of a setting of 4 parameters.

Non-adherent MOLM-13 human acute myeloid leukemia cells (DSMZ ACC 554) were seeded at a density of 5,000 cells per cavity in a 96-well microtiter plate in 100 pl of growth medium supplemented with 10% bovine fetal serum. After 24 hours, the cell viability of a plate (zero point plate) was determined with the Cell Titre-Glo luminescent cell viability test (Promega), while 50 pl of medium containing the test compound were added. the cavities of the other plates (final concentrations in the range between 0.001 and 10 pM and DMSO controls; the final concentration of the dimethylsulfoxide solvent was 0.5%). Cell viability was evaluated after a 72-hour exposure with the Cell Titre-Glo luminescent cell viability assay (Promega). The IC50 values (50% inhibitory concentration of the maximum effect) were determined by means of an adjustment of 4 measurement data parameters that were normalized to vehicle-treated cells (DMSO) (= 100%) and readings of measurements taken immediately before exposure to the compound (= 0%).

4. Flask solubility test with equilibrium agitation:

4a) Thermodynamic solubility in water

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The thermodynamic solubility of compounds in water was determined by a flask procedure with equilibrium stirring (see, for example: EH Kerns, L. Di: Drug-like Properties: Concepts, Structure Design and Methods, 276286, Burlington, MA, Academic Press, 2008). A saturated solution of the drug was prepared and the solution was mixed for 24 hours to ensure that equilibrium was reached. The solution was centrifuged to remove the insoluble fraction and the concentration of the compound in solution was determined using a standard calibration curve. To prepare the sample, 2 mg of solid compound was weighed in a 4 ml glass vial. 1 ml of phosphate buffer pH 6.5 was added. The suspension was stirred for 24 hours at room temperature. Then the solution was centrifuged. To prepare the sample for standard calibration, 2 mg of the solid sample was dissolved in 30 ml of acetonitrile. After sonication, the solution was diluted with water to 50 ml. The sample and standards were quantified by HPLC with UV detection. For each sample, two injection volumes (5 and 50 pl) were made in triplicate. Three injection volumes (5 pl, 10 pl and 20 pl) were made for the standard.

Chromatographic conditions:

HPLC column: Injection volume:

Flow:

Mobile phase:

UV detector:

Xterra EM C18 2.5 pm 4.6 x 30 mm Sample: 3x5 pl and 3x50 pl Standard: 5 pl, 10 pl, 20 pl 1.5 ml / min acid gradient:

A: water / 0.01% TFA

B: 0.01% Acetonitrile / TFA

0 min ^ A 95% B 5%

0 to 3 minutes ^ A at 35% B at 65%, linear gradient

3 to 5 minutes ^ A 35% B 65%, isocratic

5 to 6 minutes ^ A 95% B 5%, isocratic

wavelength close to maximum absorption (between 200 and 400 nm)

Injection areas of the sample and standard as well as the calculation of the solubility value (in mg / l) were determined with the use of a computer program for HPLC (Waters Empower 2 FR).

4b) Thermodynamic solubility in citrate buffer solution at pH 4

Thermodynamic solubility was determined by an equilibrated stirred vessel procedure [Literature: Edward H. Kerns and Li Di (2008) Solubility Methods in: Drug-like Properties: Concepts, Structure Design and Methods, p276-286. Burlington, MA: Academic Press].

A saturated solution of the drug was prepared and the solution was mixed for 24 h to ensure that equilibrium has been reached. The solution was centrifuged to remove the insoluble fraction and the concentration of the compound in solution was determined using a standard calibration curve.

To prepare the sample, 1.5 mg of solid compound was weighed into a 4 ml glass vial. 1 ml of citrate buffer solution was added at pH 4. The suspension was placed on a stirrer and mixed for 24 hours at room temperature. The solution was centrifuged after that. To prepare the sample for standard calibration, 0.6 mg of solid sample was dissolved in 19 ml of 1: 1 acetonitrile / water. After sonication, the solution was brought to 20 ml with 1: 1 acetonitrile / water.

The sample and standards were quantified by HPLC with UV detection. For each sample, two injection volumes (5 and 50 pl) were made in triplicate. Three injection volumes (5 pl, 10 pl and 20 pl) were made for the standard.

Chemicals:

Citrate buffer solution at pH 4 (MERCK Art. 109435; 1 L consisting of 11,768 g of citric acid, 4,480 g of sodium hydroxide, 1,604 g of hydrogen chloride)

The chromatographic conditions were as follows:

HPLC column: Injection volume:

Flow:

Mobile phase:

Xterra EM C18 2.5 pm 4.6 x 30 mm Sample: 3x5 pl and 3x50 pl Standard: 5 pl, 10 pl, 20 pl 1.5 ml / min acid gradient:

A: water / 0.01% TFA

B: 0.01% Acetonitrile / TFA

0 min: 95% of A 5% of B 0-3 min: 35% of A 65% of B, linear gradient 3-5 min: 35% of A 65% of B, isocratic 5-6 min: 95% of A 5% of B, isocratic

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UV detector: wavelength near maximum absorption (between 200 and 400 nm)

The areas of sample injections and the standard, as well as the calculation of the solubility value (in mg / l) were determined by using the HPLC program (Waters Empower 2 FR).

The areas of the sample and standard injections, as well as the calculation of the solubility value (in mg / l) were determined using the HPLC program (Waters Empower 2 FR).

5. Caco-2 permeability test

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded at a density of 4.5 x 104 cells per cavity on 24 cavity plates, 0.4 pm pore size, and grown for 15 days in medium DMEM supplemented with 10% fetal bovine serum, 1% GlutaMAX (100x, GIBCO), 100 U / ml penicillin, 100 pg / ml streptomycin (GIBCO) and 1% non-essential amino acids (100 x). The cells were kept at 37 ° C in a humidified atmosphere with 5% CO2. The medium was changed every 2-3 days. Before conducting the permeability test, the culture medium was replaced by a transport buffer solution of hepes-carbonate without FCS (pH 7.2). To assess the integrity of the monolayer, transepithelial electrical resistance (TEER) was measured. Test compounds were predisolved in DMSO and added to the apical or basolateral compartment at a final concentration of 2 pM in transport buffer solution. Samples were taken before and after 2 hours of incubation at 37 ° C of both compartments. The analysis of the compound content was carried out after a precipitation with methanol by LC / MS / MS analysis. Permeability (Papp) was calculated in the apical to basolateral (A ^ B) and basolateral to apical (B ^ A) directions. The apparent permeability was calculated using the following equation:

Papp = (Vr / Po) (1 / S) (P2 / t)

Where Vr is the volume of media in the receiving chamber, Po is the area or height of the peak measured for the test drug in the donor chamber at = o, S is the surface area of the monolayer, P2 is the peak area measurement for the test drug in the acceptor chamber after 2 hours of incubation, and t is the incubation time. The ratio of basolateral efflux (B) to apical (A) was calculated by dividing the value of Papp B-A by the value of Papp A-B. In addition the recovery of compound was calculated. The following reference compounds were used for classifying the permeability class: Antipyrine, Pirazosin, Verapamil, Fluvastatin, Cimetidine, Ranitidine, Atenolol, Sulfasalazine.

6. Carbonic anhydrase test

The principle of the test is based on the hydrolysis of 4-nitrophenyl acetate by carbonic anhydrase (Pocker & Stone, Biochemistry, 1967, 6, 668), with subsequent photometric determination of the 4-nitrophenolate marker product at 400 nm by means of a photometer 96 channel spectral.

2 pl of the test compounds, dissolved in DMSO (100 times the final concentration), were pipetted in a concentration range between 0.03 and 10 pmol / L (final), in quadruplicate to the wells of a microtiter plate. 96 wells Wells containing the solvent without the test compounds were used as reference values (1. Wells without carbonic anhydrase for correction of the non-enzymatic hydrolysis of the substrate and 2. Wells with carbonic anhydrase for the determination of non-enzyme activity inhibited)

188 pl of test buffer solution (10 mmol / L of tris / HCl, pH 7.4, 80 mmol / L of NaCl) were pipetted, with or without 3 units / well of carbonic anhydrase 1 [= human carbonic anhydrase -1 (Sigma, No. C4396)] with the objective of determining the inhibition of carbonic anhydrase-1 or 3 units / well of carbonic anhydrase-2 [= human carbonic anhydrase 2 (Sigma, No. C6165)] to measure the inhibition of carbonic anhydrase 2, in the wells of the microtiter plate. The enzymatic reaction was extended with the addition of 10 microliters of the substrate solution (1 mmol / L of 4-nitrophenyl acetate (Fluka No. 4602), dissolved in anhydrous acetonitrile (final substrate concentration: 50 pmol / L). The plate was incubated at room temperature for 15 minutes. Absorption by photometry was measured at a wavelength of 400 nm. Enzyme inhibition was calculated after normalizing the values measured by the absorption of the reactions in the wells without enzyme (= 100% inhibition) and by absorbing the reactions in the wells with uninhibited enzyme (= 0% inhibition) IC50 values were determined by means of a 4 parameter setting using the company's own program.

Preparative Examples

Composites Synthesis

The synthesis of the N- (pyridin-2-yl) pyrimidin-4-amine derivatives according to the present invention is preferably carried out according to the general synthetic sequences, which are shown in Schemes 1 to 4.

In addition to those routes described below, other routes can also be used to synthesize the target compounds, in accordance with the general common knowledge of a person skilled in the art of

organic synthesis. The order of the transformations exemplified in the following Schemes is therefore not intended to be limiting, and the appropriate synthesis steps of the different schemes can be combined to form additional synthesis sequences. In addition, the interconversion of any of the substituents R1, R2, R3, R4 and / or R5 can be achieved before and / or after the exemplified transformations.

5 These modifications may be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metalation, metal catalyzed coupling reactions, substitution or other reactions known to a person skilled in the art. These transformations include those that introduce functionality that allows other subconversions of substituents. Appropriate protective groups and their introduction and cleavage are well known to a person skilled in the art (see, 10 for example, T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs. Additionally, it is possible to carry out two or more successive steps without carrying out a purification between said steps, for example, a reaction of "a container", as is well known by a person skilled in the art.

The geometry of the sulfoximin group makes the compounds of the general formula (I) chiral. The separation of the 15 racemic sulfoximins in their enantiomers can be achieved by methods known to a person skilled in the art, preferably by means of preparative HPLC on chiral stationary phase.

Scheme 1 illustrates a preferred synthetic strategy for the compounds of general formula (I). In the first step, 4,6-dichloropyrimidine (CAS No .: 1193-21-1; 1) is reacted with a boronic acid derivative R2-B (OR) 2 of formula (2), in which R2 it is as defined for the compound of general formula (I), to give a compound of formula (3). The boronic acid derivative (2) may be a boronic acid (R = -H) or an ester of the boronic acid, for example, its isopropyl ester (R = -CH (CH3) 2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RR = -C (CH3) 2-C (CH3) 2-).

N ^ N

II

Cl

Cl

R-O

B-R2

R-O

N ^ N

II

Cl

R2

N ^ N

Cl

R

1 / S

image33

NH

image34

R4

R '

R

‘N N ^ N

II II

"N *

I

5 h

"R2

image35

H

2

one

3

3

R

3

R

4

S

2

2

R

R

R

3

5

F

2

5

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25

30

35

40

F

image36

6 h

2

 R3

 R \

 HN O N

 N ^ N

 \ V / r ^ s \ .A ^ A

 ■ N ^ R2 1

 (I); R5 = H

 1 HOUR

R

R

HN O

I / O

image37

(I), R5 = H

-,5

R

\ R '

NO

\\ //

image38

(I)

3

R

3

R

2

R

2

R

Scheme 1

The coupling reaction is catalyzed by palladium catalysts, for example, by Pd (0) catalysts such as fefragu / s (triphenylphosphine) palladium (0) [Pd (PPh3) 4], tris (dibenzylideneacetone) di-palladium (0) [Pd2 (dba) 3], or by Pd (II) catalysts such as dichlorobis (triphenylphosphine) -palladium (II) [Pd (PPh3) 2Cy, palladium (II) acetate and triphenylphosphine or by [1,1 'dichloride -bis (diphenylphosphino) ferrocene] palladium.

The reaction is preferably carried out in a mixture of a solvent such as 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base such as potassium carbonate, sodium bicarbonate or potassium phosphate .

(revision: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and the references cited therein).

The reaction is carried out at temperatures in the range between room temperature (ie approximately 20 ° C) and the boiling point of the respective solvent. In addition, the reaction can be carried out at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time.

In the second step, a compound of formula (3) is reacted, in which R2 is as defined for the compound of general formula (I), with a suitable pyridin-2-amine of formula (4), in which that R1, R3 and R4 are as defined for the compound of general formula (I), to give a compound of formula (5). This coupling reaction can be carried out by a C-N cross-coupling reaction catalyzed by Palladium (for a review on C-N cross-coupling reactions see, for example: a) L. Jiang, S.L. Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', 2nd ed .: A. de Meijere, F. Diederich, Eds .: Wiley-VCH: Weinheim, Germany, 2004).

The use described herein of tris (dibenzylideneacetone) dipaladium (0), (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane) and cesium carbonate in dioxane is preferred. The reactions are preferably carried out in an argon atmosphere between 3 and 48 hours at 100 ° C in a microwave oven or in an oil bath.

The pyridine-2-amines of formula (4) are commercially available in certain cases, or they can be prepared by methods known to persons skilled in the art, for example, from the corresponding 4-hydroxymethylpyridine-2- amine through the conversion of the hydroxyl group contained therein to a suitable leaving group, such as chlorine or bromine, followed by nucleophilic displacement with a thiol of general formula (10). If necessary, the amino group present in said 4-hydroxymethylpyridine-2-amine can be protected with a suitable protecting group. The protective groups for amino groups present in the analogs and the procedures for their introduction and withdrawal are well known to people with experience in the field, see, for example, T.W. Greene and P.G.M. Wuts in: Protective Groups in Organic Synthesis, 3rd edition, Wiley (1999).

In the third step, the imination of a compound of formula (5) gives the corresponding sulfilimine of formula (6) (see, for example: a) C. Bolm et al., Organic Letters, 2004, 6, 1305; b) J. Kruger et al., WO 2012/038411). Said imination is carried out by reacting a compound of formula (5) with trifluoroacetamide and a suitable oxidant, such as 1,3-dibromo-5,5-dimethylhydantoin in the presence of an alkaline salt of ferc-butanol, such as ferc -sodium butoxide, in a cyclic ether, such as tetrahydrofuran and dioxane, or mixtures thereof, as solvent.

Oxidation of the sulfilimine of formula (6) followed by deprotection of the trifluoroacetyl group gives the N-deprotected sulfoximin of formula (I) (see, for example: a) A. Plant et al., WO 2006/037945; b) J. Kruger et al., WO 2012/038411). Said oxidation is carried out by reacting the compounds of formula (6) with an alkaline salt

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Four. Five

of parmanganic acid, such as potassium permanganate, in an aliphatic ketone of formula Ci-C2-C (O) -Ci-C2-alkyl, such as acetone, as solvent. Unless the trifluoroacetyl group present in the compounds of formula (6) has been removed by cleavage during the oxidation process mentioned above, it can be removed by treating the resulting intermediate with a suitable base, such as a carbonate of an alkali metal or alkaline earth metal, preferably potassium carbonate, in a suitable alcohol, such as a C1-C6-OH alkyl aliphatic alcohol, preferably methanol.

Said oxidation is also preferably carried out by reacting compounds of formula (6) with a peroxomonosulfate-based oxidant, such as Oxone® (CAS No. 37222-66-5), in a mixture of suitable solvents, such as methanol / water and as required by additional DMF circumstances, while controlling the pH of the reaction mixture with aqueous potassium hydroxide solution to give the N-deprotected sulfoximin of formula (I) (R5 = H).

The pyridine-2-amines of formula (4) are commercially available in certain cases, or they can be prepared by methods known to persons skilled in the art, for example, from the corresponding 4-hydroxymethylpyridine-2- amine through the conversion of the hydroxyl group contained therein to a suitable leaving group such as chlorine or bromine, followed by nucleophilic displacement with a thiol of general formula R1-SH, in which R1 is defined as defined for the compound of general formula (I). If necessary, the amino group present in said 4-hydroxymethylpyridine-2-amine can be protected with a suitable protecting group. The protective groups for amino groups present in the analogs and the procedures for their introduction and withdrawal are well known to people with experience in the field, see, for example, T.W. Greene and P.G.M. Wuts in: Protective Groups in Organic Synthesis, 3s edition, Wiley (1999).

The thiols of formula R1-SH are known to the person skilled in the art and are commercially available in a considerable variety.

The N-deprotected sulfoximins of formula (I) can be reacted to give N-functionalized derivatives of formula (I). There are multiple procedures for the preparation of N-functionalized sulfoximins by functionalization of the sulfoximin group nitrogen:

- Rental: see, for example: a) U. Lucking et al., US 2007/0232632; b) C.R. Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al., Synthesis 2009, 10, 1601.

- Acylation: see, for example: a) C. Bolm et al., Chem. Europ. J. 2004, 10, 2942; b) C. Bolm et al., Synthesis 2002, 7, 879; c) C. Bolm et al., Chem. Europ. J. 2001,7, 1118.

- Arilacion: see, for example: a) C. Bolm et al., Tet. Lett. 1998, 39, 5731; b) C. Bolm et al., J. Org. Chem. 2000,

65, 169; c) C. Bolm et al., Synthesis 2000, 7, 911; d) C. Bolm et al., J. Org. Chem. 2005, 70, 2346; e) U. Lucking

et al., WO2007 / 71455.

- Reaction with isocyanates: see, for example: a) V.J. Bauer et al., J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al., J. Am. Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al., Acta Chem. Scand. Ser. B 1983, 325; d) U. Lucking et al., US2007 / 0191393.

- Reaction with sulfonylchlorides: see, for example: a) D.J. Cram et al., J. Am. Chem. Soc. 1970, 92, 7369; b)

C.R. Johnson et al., J. Org. Chem. 1978, 43, 4136; c) A.C. Barnes, J. Med. Chem. 1979, 22, 418; d) D. Craig and

col., Tet. 1995, 51,6071; e) U. Lucking et al., US2007 / 191393.

- Reaction with chloroformates: see, for example: a) P.B. Kirby et al., DE2129678; b) D.J. Cram et al., J. Am. Chem. Soc. 1974, 96, 2183; c) P. Stoss et al., Chem. Ber. 1978, 111, 1453; d) U. Lucking et al., WO2005 / 37800.

- Reaction with bromocyanate: see, for example: a) D.T. Sauer et al., Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al., Org. Lett. 2007, 9, 2951; c) U. Lucking et al., WO 2011/29537.

An alternative synthesis strategy for N- (pyridin-2-yl) pyrimidin-4-amine derivatives according to the present invention is described in Scheme 2.

R '

,3

image39

H

3

8

5

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R

HO

R3

image40

N

‘R2

R

LG

R3

image41

N

R2

R '

LG

R3

image42

N

'R2

R — SH 10

R '

R

R3

image43

R2

8

9

9

5

Scheme 2

In the first step, a compound of formula (3), wherein R2 is as defined for the compound of general formula (I), is reacted with a suitable pyridin-2-amine of formula (7), in the that R3 and R4 are as defined for the compound of general formula (I), to give a compound of formula (8). This coupling reaction can be carried out by a C-N cross-coupling reaction catalyzed by Palladium (for a review on C-N cross-coupling reactions see, for example: a) L. Jiang, S.L. Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', 2nd ed .: A. de Meijere, F. Diederich, Eds .: Wiley-VCH: Weinheim, Germany, 2004). The use described herein of tris (dibenzylideneaketone) dipaladium (0), (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane) and cesium carbonate in dioxane is preferred. The reactions are preferably carried out in an argon atmosphere between 3 and 48 hours at 100 ° C in a microwave oven or in an oil bath. The pyridine-2-amines of formula (7) are commercially available in certain cases, or they can be prepared by procedures known to persons skilled in the art, for example, by reduction of the corresponding carboxylic acids or esters of the same.

In the second step, a compound of formula (8), in which R2, R3 and R4 are as defined for the compound of general formula (I), is converted to a compound of formula (9), in which R2 , R3 and R4 are as defined for the compound of general formula (I) and in which LG represents a leaving group, preferably chlorine or bromine. The use described herein is thionyl chloride in NMP or DMF and DCM for the formation of the respective chloromethyl pyridines (LG = Cl). One possibility for the formation of the respective bromomethyl pyridines (LG = Br) is the use of tetrabromomethane and triphenylphosphane in DCM (see, for example: Polla et al., Bioorganic and Medicinal Chemistry, 2004, 12, 1151).

In the third step, a compound of formula (9) is converted to a thioester of formula (5), in which R1, R2, R3 and R4 are as defined for the compound of general formula (I), by reaction with suitable thiols of formula (10), wherein R 1 is as defined for the compound of formula (I), under basic conditions, yielding the corresponding thioethers of formula (5) (see, for example: Sammond et al., Bioorg. Med. Chem. Lett. 2005, 15, 3519). The thiols of formula (10) are known to persons with experience in the field and are available in the market in a considerable variety.

In the final steps, the thioether of formula (5) is converted to the corresponding sulfoximin of formula (I) as described in Scheme 1.

Another alternative synthetic strategy for N- (pyridin-2-yl) pyrimidin-4-amine derivatives according to the present invention is described in Scheme 3.

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R-O

\ 2

B-R2

R-O

N

II

H2N '^ Cl

eleven

N ^ N

R '

+

H2N '^' R "

HO

image44

LG

N ^ N

image45

R2

R

HO

image46

N

12

13

2

3

R

2

R

8

Scheme 3

In the first step, 6-chloropyrimidin-4-amine (CAS No. 5305-59-9; 11) is reacted with a boronic acid derivative R2-B (OR) 2 of formula (2), in the that R2 is as defined for the compound of general formula (I), to give a compound of formula (12). The boronic acid derivative (2) may be a boronic acid (R = -H) or an ester of the boronic acid, for example, its isopropyl ester (R = -CH (CH3) 2), preferably an ester derived from pinacol wherein the boronic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (RR = -C (CH3) 2-C (CH3) 2-).

The coupling reaction is catalyzed by palladium catalysts, for example, by Pd (0) catalysts such as fefragu / s (triphenylphosphine) palladium (0) [Pd (PPh3) 4], tris (dibenzylideneacetone) di-palladium (0) [Pd2 (dba) 3], or by Pd (II) catalysts such as dichlorobis (triphenylphosphine) -palladium (II) [Pd (PPh3) 2Cy, palladium (II) acetate and triphenylphosphine or by [1,1 'dichloride -bis (diphenylphosphino) ferrocene] palladium.

The reaction is preferably carried out in a mixture of a solvent such as 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with water and in the presence of a base such as potassium carbonate, sodium bicarbonate or potassium phosphate .

(revision: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and the references cited therein).

The reaction is carried out at temperatures in the range between room temperature (ie approximately 20 ° C) and the boiling point of the respective solvent. In addition, the reaction can be carried out at temperatures above the boiling point using pressure tubes and a microwave oven. The reaction is preferably completed after 1 to 36 hours of reaction time.

In the second step, a compound of formula (12) is reacted, in which R2 is as defined for the compound of general formula (I), with a suitable pyridine of formula (13), in which R1, R3 and R4 are as defined for the compound of general formula (I) and wherein LG represents a leaving group, such as chlorine or bromine, to give a compound of formula (8). This coupling reaction can be carried out by a C-N cross-coupling reaction catalyzed by Palladium (for a review on C-N cross-coupling reactions see, for example: a) L. Jiang, S.L. Buchwald in 'Metal-Catalyzed Cross-Coupling Reactions', 2nd ed .: A. de Meijere, F. Diederich, Eds .: Wiley-VCH: Weinheim, Germany, 2004).

The use described herein of tris (dibenzylideneacetone) dipaladium (0), (9,9-dimethyl-9H-xanthene-4,5-diyl) bis (diphenylphosphane) and cesium carbonate in dioxane is preferred. The reactions are preferably carried out in an argon atmosphere between 3 and 48 hours at 100 ° C in a microwave oven or in an oil bath.

In subsequent steps, the benzyl alcohol of formula (8) is first converted to the corresponding thioether of formula (5) as described in Scheme 2 and then transformed to the corresponding sulfoximin of formula (I) as described in Scheme one.

The pyridine derivatives of formula (13) are known to persons skilled in the art and are available in the market in a considerable variety.

Another alternative synthesis strategy for the N- (pyridin-2-yl) pyrimidin-4-amine derivatives of formula (I) according to the present invention is described in Scheme 4.

R3

N

II

R

image47

R3

LG

R

H2N v R "

12

R

image48

N

R2

5

Scheme 4

A compound of formula (12) is reacted with an appropriate pyridine derivative of formula (14), in which R1, R3 and R4 are as defined for the compound of general formula (I) and in which LG represents a leaving group 5, preferably chlorine, to give a compound of formula (5). This coupling reaction can be carried out by a C-N cross-coupling reaction catalyzed by Palladium (for a review on C-N cross-coupling reactions see, for example: a) L. Jiang, S.L. Buchwald in 'Metal-Catalyzed CrossCoupling Reactions', 2nd ed .: A. de Meijere, F. Diederich, Eds .: Wiley-VCH: Weinheim, Germany, 2004).

The use described herein of the chloro (2-dicyclohexylphosphino-2 ', 4', 6'-tri-iso-propyl-10 1,1'-biphenyl) [2- (2-aminoethyl) phenyl adduct is preferred ] Palladium (II) methyl-ferc-butyleter, 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl and potassium phosphate in toluene and NMP. The reactions are preferably carried out in an argon atmosphere between 2 and 24 hours at between 100 and 130 ° C in a microwave oven or in an oil bath.

In the final steps, the thioether of formula (5) is converted to the corresponding sulfoximin of formula (I) as described in Scheme 1.

The pyridine derivatives of formula (14) can be prepared according to procedures known to persons skilled in the art, for example, by converting a halomethyl group to the thioether present in the compound of formula (14) using a thiol of formula (10), wherein R 1 is as defined for the compound of general formula (I), in a similar manner as previously described for pyridine amines of formula (4) and for the conversion of formula intermediates (9) in the thioethers of formula (5) of Scheme 2. Said precursors of halomethyl pyridine are known to persons skilled in the art and are commercially available in certain cases.

Preparation of the compounds:

The abbreviations used in the description of chemistry and in the Examples that follow are:

25 to (width); CDCL (deuterated chloroform); cHex (cyclohexane); d (double); DCM (dichloromethane); DIPEA (di-iso-propylethylamine); DME (1,2-dimethoxyethane), DMF (dimethylformamide); DMSO (dimethyl sulfoxide); equiv. (equivalent); ES (electroatomized); EtOAc (ethyl acetate); EtOH (ethanol); iPrOH (iso-propanol); mCPBA (meta-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH (methanol); MS (mass spectrometry); NBS (N-bromosuccinimide), NMP (N-Methyl-pyrrolidin-2-one); NMR (nuclear magnetic resonance); Oxone® (triple salt of 2KHSO5 * KHSO4 * K2SO4); p (pentet); Pd (dppf) Cl2 complex ([1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (II) with

dichloromethane); iPrOH (iso-propanol); q (quartet); TA (room temperature); s (singlet); sat. ac. (saturated aqueous); SiO2 (silica gel); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran); tr (triplet); trd (double triplet).

The IUPAC names of the examples were generated using the 'ACD / Name batch version 12.01' program of ACD 35 LABS.

Example 1:

(rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine

image49

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Intermediary Preparation 1.1:

4-Chloro-6- (4-fluoro-2-methoxyphenyl) pyrimidine

Cl

image50

F

In an argon atmosphere, a mixture of 4,6-dichloropyrimidine (5.00 g; 33.56 mmol), boronic acid (4-fluoro-2-methoxyphenyl) (6.27 g; 36.92 mmol; Aldrich Chemical Company Inc.) and [1,1 '-bis-

(diphenylphosphino) ferrocen] dichloropaladium (II) (2.74 g; 3.36 mmol; Aldrich Chemical Company Inc.) in an aqueous solution of 2M potassium carbonate (50 ml) and 1,2-dimethoxyethane (101 ml) stirred for 150 minutes at 90 ° C. After cooling, the batch was diluted with ethyl acetate and washed with dilute aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (5% hexane / ethyl acetate to 40% hexane / ethyl acetate) to give the desired product (6.35 g; 26.61 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 9.00 (m, 1H), 8.13 (m, 1H), 8.02 (m, 1H), 6.82 (m, 1H), 6, 75 (m, 1H), 3.94 (s, 3H).

Intermediary Preparation 1.2:

6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(methylsulfanyl) methyl] pyridin-2-yl} pyrimidin-4-amine

image51

A batch with 4-chloro-6- (4-fluoro-2-methoxyphenyl) pyrimidine (475 mg; 1.99 mmol), 4 - [(methylsulfanyl) methyl] pyridin-2-amine (614 mg; 3.98 mmol ; ukrOrgSynthesis Ltd.), (9,9-dimethyl-9H-xanthen-4,5-diyl) bis (diphenylphosphane) (51 mg; 0.09 mmol) and cesium carbonate (972 mg; 2.99 mmol) in Dioxane (7.1 ml) was degassed using argon. Tris (dibenzylidenacetone) dipaladium (0) (27 mg; 0.03 mmol) was added in an argon atmosphere and the batch was stirred in a closed pressure tube for 8 hours at 100 ° C. After cooling, more (9,9-dimethyl-9H-xanthen-4,5-diyl) bis (diphenylphosphane) (17 mg; 0.03 mmol) and tris (dibenzylidenacetone) dipaladium (0) (9 mg; 0.01 mmol) in an argon atmosphere and the mixture was stirred in a closed pressure tube for 14 hours at 100 ° C.

After cooling, the batch was diluted with DCM and filtered. The solids were washed with DCM and the combined filtered materials were concentrated. The residue was purified by chromatography (DCM / EtOH 95: 5) to give the desired product (424 mg; 1.19 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 8.86 (m, 1H), 8.26 (m, 1H), 8.04 (m, 1H), 7.94 (m, 1H), 7, 82 (s, 1H), 7.76 (a, 1H), 6.96 (m, 1H), 6.77 (m, 2H), 3.92 (s, 3H), 3.67 (s, 2H ), 2.06 (s, 3H).

Intermediary Preparation 1.3:

2,2,2-Trifluoro-N - {[(2 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methyl] (methyl) -A4- sulfaniliden}

acetamide

F

image52

F

In an argon atmosphere, a solution of 2,2,2-trifluoroacetamide (200 mg; 1.77 mmol) in THF (1.0 ml) was added dropwise to a solution of sodium ferc-butoxide (113 mg; 1.18 mmol) in THF (0.8 ml), such that the temperature of the mixture was kept below 10 ° C. Then, a newly prepared solution of

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30

1,3-dibromo-5,5-dimethylhydantoin (253 mg; 0.88 mmol) in THF (1.5 ml) drip to the stirred mixture, such that the temperature of the mixture was kept below 10 ° C. Then the mixture was stirred for 10 minutes at 10 ° C. Finally, a solution of 6- (4-fluoro-2-methoxyphenyl) -N- {4 - [(methylsulfanyl) methyl] pyridin-2- yl} pyrimidin-4-amine (420 mg; 1.18 mmol) was added. in dioxane (10.0 ml) by dripping to the stirred mixture, such that the temperature of the mixture was kept below 10 ° C. The mixture was stirred for 75 minutes at 10 ° C. The batch was diluted with toluene (2.0 ml) with cooling and an aqueous solution of sodium sulphite (149 mg; 1.18 mmol in 2.0 ml water) was added such that the temperature of the mixture was maintained. below 15 ° C. An aqueous solution of sodium chloride was added and the batch was extracted with ethyl acetate (3x). The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (DCM / EtOH 94: 6) to give the desired product (348 mg; 0.74 mmol).

1H NMR (400 MHz, CDCl3, 300K) 5 = 8.90 (s, 1H), 8.38 (m, 1H), 8.28 (m, 1H), 8.11 (m, 1H), 7, 72 (s, 1H), 7.64 (s, 1H), 6.95 (m, 1H), 6.84 (m, 1H), 6.78 (m, 1H), 4.53 (d, 1H ), 4.31 (d, 1H), 3.95 (s, 3H), 2.74 (s, 3H).

Intermediary Preparation 1.4:

2,2,2-Trifluoro-N - {[(2 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methyl] (methyl) oxide-A6 -

sulfaniliden} acetamide

F

image53

Potassium permanganate (230 mg; 1.46 mmol) was added to a stirring solution of 2,2,2-trifluoro-N - {[(2 - {[6- (4- fluoro-2-methoxyphenyl) pyrimidine- 4-yl] amino} pyridin-4-yl) methyl] (methyl) -A4-sulfanyliden} acetamide (340 mg; 0.73 mmol) in acetone (3.4 ml) at Ta. The mixture was stirred at 50 ° C for 5 hours, then potassium permanganate (115 mg; 0.73 mmol) was added and stirring was continued at 50 ° C. After 90 minutes, more potassium permanganate (115 mg; 0.73 mmol) was added and stirring was continued at 50 ° C. After 90 minutes, a solution of potassium permanganate (230 mg; 0.146 mmol) in acetone (10 ml) was added and stirring was continued at 50 ° C. After 7 hours, a solution of potassium permanganate (115 mg; 0.73 mmol) in acetone (10 ml) was added and stirring was continued at 50 ° C for 4 hours.

After cooling, the batch was filtered and the residue was washed with acetone. The combined filtered materials were concentrated. MeOH (100 ml) was added and the mixture was filtered. The filtrate was concentrated to give the crude product (180 mg) that was used without further purification.

Preparation of the final product:

Potassium carbonate (29 mg; 0.21 mmol) was added to a solution of 2,2,2-trifluoro-N - {[(2 - {[6- (4-fluoro-2- methoxyphenyl) pyrimidin-4- il] amino} pyridin-4-yl) methyl] (methyl) oxido-A6-sulfaniliden} acetamide (50 mg) in methanol (9 ml) at RT. The mixture was stirred for 50 minutes before adding water (100 ml) and the mixture was extracted with DCM / 2-propanol (4: 1) and ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (11 mg; 0.03 mmol).

 System:

 Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, SQD 3100

 Column:

 XBrigde C18 5 pm 100x30 mm

 Solvent:

 A = H2O + 0.2% NH3 (32%)

 B = MeCN

 Gradient:

 0-8 min B at 15-50%

 Flow:

 50 ml / min

 Temperature:

 TA

 Solution:

 32 mg / 3 ml DMF / MeOH 2 + 1

 Injection:

 4 x 0.75 ml

 Detection:

 DAD scan interval 210-400 nm

 EM IEN +, IEN-, scan interval 160-1000 m / z

 Retention:

 5.05 - 5.58 min

 MS (ES +):

 m / z = 387

1H NMR (400 MHz, da-DMSO, 300K) 5 = 10.28 (s, 1H), 8.75 (m, 1H), 8.35 (a, 1H), 8.31 (m, 1H), 8.04 (m, 1H), 7.87 (a, 1H), 7.09 (m, 2H), 6.91 (m, 1H), 4.42 (m, 2H), 3.93 (s , 3H), 3.77 (s, 1H), 2.90 (s, 3H).

5 Alternative procedure for the preparation of Intermediary 1.2:

6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(methylsulfanyl) methyl] pyridin-2-yl} pyrimidin-4-amine

r ^^ N N '

NO

image54

Preparation of Intermediary 1.5:

10 (2 - {[6- (4-Fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methanol

HO

N ^ N O '

image55

F

F

A batch with 4-chloro-6- (4-fluoro-2-methoxyphenyl) pyrimidine (383 mg; 1.61 mmol), (2-aminopyridin-4-yl) methanol (199 mg; 1.61 mmol; ABCR GmbH & CO. KG), (9,9-dimethyl-9H-xanthen-4,5-diyl) bis (diphenylphosphane) (418 mg; 0.72 mmol) and cesium carbonate (785 mg; 2.41 mmol) in Dioxane (8.0 ml) was degassed using argon. 15 tris (dibenzylidenacetone) dipaladium (0) (147 mg; 0.16 mmol) was added in an argon atmosphere and the batch was stirred for 5 hours at 100 ° C. After cooling, the batch was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM / EtOH 93: 7) to give the desired product (97 mg; 0.30 mmol).

1H NMR (400 MHz, da-DMSO, 300K) 5 = 10.14 (s, 1H), 8.71 (m, 1H), 8.34 (s, 1H), 8.20 (m, 1H), 8.00 (m, 1H), 7.77 20 (s, 1H), 7.06 (m, 1H), 6.88 (m, 2H), 5.36 (tr, 1H), 4.49 ( d, 2H), 3.89 (s, 3H).

Preparation of the final product (Alternative preparation of Intermediary 1.2):

Thionyl chloride (80 mg; 0.66 mmol) was added dropwise to a stirring solution of (2 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4- il) methanol (87 mg; 0.27 mmol) in DCM (1.5 ml) and NMP (0.2 ml) at 0 ° C. The mixture was stirred for 17 hours at RT. The batch was diluted with ethyl acetate, weakly basified with aqueous sodium bicarbonate solution and washed with aqueous sodium chloride solution. The aqueous layer was extracted with DCM (2x). The combined organic layers were filtered using a Whatman filter and concentrated to give crude N- [4- (chloromethyl) pyridin-2-yl] -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine, which It was used without further purification in the next step. The residue was dissolved in EtOH (2.0 ml) and the resulting solution was cooled to 0 ° C. Sodium methantiolate (22 mg; 0.32 mmol) was added to the solution under stirring at 0 ° C. The mixture was stirred for 28 hours at 30 RT before being diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane / ethyl acetate 3: 2) to give the desired product (49 mg; 0.14 mmol).

1H NMR (400 MHz, CDCla, 300K) 5 = 8.86 (m, 1H), 8.26 (m, 1H), 8.02 (m, 2H), 7.94 (m, 1H), 7, 83 (s, 1H), 6.96 (m, 1H), 6.77 (m, 2H), 3.91 (s, 3H), 3.67 (s, 2H), 2.05 (s, 3H ).

Example 2 and 3:

Enantiomers of 6- (4-fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine

image56

(Rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine (33 mg) was separated into the 5 enantiomers by preparative chiral HPLC.

 System:

 Sepiatec: Prep SFC100,

 Column:

 Chiralpak IA 5 pm 250x20 mm

 Solvent:

 CO2 / MeOH (+ 0.4% DEA) 6: 4

 Flow:

 80 ml / min

 Pressure (output)

 15 MPa (150 bar)

 Temperature:

 40 2C

 Solution:

 33 mg / 2 ml DMF

 Injection:

 20 x 0.1 ml

 Detection:

 UV 254 nm

 Retention time in min purity in% yield

 Example 2 Enantiomer 1

 2.90 - 3.50 96 12 mg (0.03 mmol)

 Example 3 Enantiomer 2

 3.65 - 4.50 94 13 mg (0.03 mmol)

Example 4:

(rac) -N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

Cl

image57

F

10 Preparation of Intermediary 4.1:

6- (4-Fluoro-2-methoxyphenyl) pyrimidin-4-amine

H2N

image58

F

5

10

fifteen

twenty

25

30

35

In an atmosphere of argon, a mixture of 6-chloropyrimidin-4-amine (500 mg; 3.86 mmol; ABCR GmbH & CO. KG), boronic acid (4-fluoro-2-methoxyphenyl) (722 mg; 4, 25 mmol; Aldrich Chemical Company Inc.) and [1,1'-bis- (diphenylphosphino) ferrocen] dichloropaladium (II) (315 mg; 0.39 mmol; Aldrich Chemical Company Inc.) in an aqueous solution of potassium carbonate 2M (5.8 ml) and 1,2-dimethoxyethane (11.6 ml) was stirred for 150 minutes at 90 ° C. After cooling, the batch was diluted with ethyl acetate and THF and washed with dilute aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane to ethyl acetate) to give the desired product (636 mg; 2.90 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 8.35 (m, 1H), 7.89 (m, 1H), 7.01 (m, 1H), 6.96 (m, 1H) 6.83 (m, 1H), 6.78 (a, 2H), 3.84 (s, 3H).

Intermediary Preparation 4.2:

(2-Chloro-6 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methanol

Cl

image59

F

A batch containing 6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine (500 mg; 2.28 mmol), (2,6-dichloropyridin-4-yl) methanol (609 mg; 3.42 mmol ; ABCR GmbH & CO. KG), (9,9-dimethyl-9H-xanthen-4,5-diyl) bis (diphenylphosphane) (67 mg; 0.07 mmol) and cesium carbonate (892 mg; 2.73 mmol) in dioxane (5.3 ml) was degassed using argon. Tris (dibenzylidenacetone) dipaladium (0) (67 mg; 0.07 mmol) was added in an argon atmosphere and the mixture was stirred in a closed pressure tube for 8 hours at 100 ° C. After cooling, more (9,9-dimethyl-9H-xanthen-4,5-diyl) bis (diphenylphosphane) (17 mg; 0.03 mmol) and tris (dibenzylidenacetone) dipaladium (0) (9 mg; 0.01 mmol) in an argon atmosphere and the mixture was stirred in a closed pressure tube for 75 minutes at 100 ° C.

After cooling, the batch was diluted with aqueous sodium chloride solution and extracted with ethyl acetate / THF. The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (hexane to ethyl acetate) to give the desired product (321 mg; 0.89 mmol).

1H NMR (400 MHz, da-DMSO, 300K) 5 = 10.47 (s, 1H), 8.78 (m, 1H), 8.27 (s, 1H), 8.05 (m, 1H), 7.83 (s, 1H), 7.08 (m, 1H), 6.97 (s, 1H), 6.89 (m, 1H), 5.51 (tr, 1H), 4.50 (d , 2H), 3.91 (s, 3H).

Intermediary Preparation 4.3:

N- [6-Chloro-4- (chloromethyl) pyridin-2-yl] -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

Cl

image60

Thionyl chloride (289 mg; 2.43 mmol) was added dropwise to a stirring solution of (2-chloro-6 - {[6- (4-fluoro-2- methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methanol (350 mg; 0.97 mmol) in DMF (10.5 ml) at 0 ° C. The mixture was stirred for 2 hours at RT. The batch was diluted with ethyl acetate, weakly basified with aqueous sodium bicarbonate solution and washed with aqueous sodium chloride solution. The aqueous layer was extracted twice (2x) with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated to give the desired product (156 mg; 0.41 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 8.88 (m, 1H), 8.11 (m, 1H), 7.97 (m, 1H), 7.87 (s, 1H), 7, 78 (s, 1H), 7.03 (s, 1H), 6.80 (m, 1H), 6.74 (m, 1H), 4.54 (s, 2H), 3.95 (s, 3H ).

5

10

fifteen

twenty

25

30

Intermediary Preparation 4.4:

N- {6-Chloro-4 - [(methylsulfanyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

Cl

image61

F

An aqueous solution of sodium methantiolate (21%; 0.16 ml; Aldrich Chemical Company Inc.) was added to the stirring solution of N- [6-chloro-4- (chloromethyl) pyridin-2-yl] -6 - (4-Fluoro-2-methoxyphenyl) pyrimidin-4-amine (154 mg; 0.41 mmol) in acetone (4.9 ml) at 0 ° C. The mixture was stirred overnight at RT before being diluted with an aqueous solution of sodium chloride and extracted twice with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (hexane to hexane / 50% ethyl acetate) to give the desired product (98 mg; 0.25 mmol).

NMR (400 MHz, CDCls, 300K) 5 = 8.88 (s, 1H), 8.11 (m, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 6.98 (s, 1H), 6.77 (m, 2H), 3.96 (s, 3H), 3.64 (s, 2H), 2.07 (s, 3H) .

Preparation of Intermediary 4.5:

(rac) -N - {[(2-Chloro-6 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methyl] (methyl) -A4- sulfaniliden} -

2,2,2-trifluoroacetamide

F

image62

F

Intermediary 4.5 was prepared under similar conditions as described in the preparation of Intermediary 1.3 using N- {6-chloro-4 - [(methylsulfanyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) ) pyrimidin-4-amine.

1H NMR (400 MHz, CDCls, 300K) 5 = 8.88 (s, 1H), 8.13 (m, 2H), 7.78 (s, 1H), 7.60 (s, 1H), 6, 94 (s, 1H), 6.81 (m, 1H), 6.76 (m, 1H), 4.43 (d, 1H), 4.28 (d, 1H), 3.95 (s, 3H ), 2.75 (s, 3H).

Preparation of the final product:

A solution of potassium permanganate (33 mg; 0.21 mmol) in acetone (1.1 ml) was added to a stirring solution of (rac) -N - {[(2-chloro-6 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methyl] (methyl) -A4-sulfanyliden} -

2,2,2-trifluoroacetamide (52 mg; 0.10 mmol) in acetone (0.5 ml) at RT. The mixture was stirred at 50 ° C overnight, before adding a solution of potassium permanganate (65 mg; 0.41 mmol) in acetone (2.2 ml) and stirring was continued at 50 ° C for 16 hours. . After cooling, the batch was filtered and the residue was washed with acetone and ethanol. The combined filtered materials were concentrated.

The residue was dissolved in MeOH (4.7 ml), potassium carbonate (15 mg; 0.11 mmol) was added and the reaction mixture was stirred for 75 minutes at RT. The batch was diluted with THF / ethyl acetate 3: 1 and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (3 mg; 0.01 mmol).

 System:

 Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, SQD 3100

 Column:

 XBrigde C18 5 pm 100x30 mm

 Solvent:

 A = H2O + 0.1% HCOOH (99%)

 B = MeCN

 Gradient:

 0-8 min B at 15-50%

 Flow:

 50 ml / min

 Temperature:

 TA

 Solution:

 49 mg / 2 ml DMF / MeOH 1: 1

 Injection:

 2 x 1 ml

 Detection:

 DAD scan interval 210-400 nm

 EM IEN +, IEN-, scan interval 160-1000 m / z

 Retention:

 5.83 - 6.19 min

 MS (ES +):

 m / z = 421

1H NMR (400 MHz, da-DMSO, 300K) 5 = 10.58 (s, 1H), 8.78 (m, 1H), 8.26 (s, 1H), 8.05 (m, 1H), 7.88 (s, 1H), 7.11 (s, 1H), 7.07 (m, 1H), 6.89 (m, 1H), 4.43 (s, 2H), 3.91 (s , 3H), 3.88 (s, 1H), 2.88 (s, 3H).

5 Alternative preparation of the final product: (LUEK 4457-3)

An aqueous solution of potassium hydroxide (25%) was added dropwise to a stirring solution of (rac) -N - {[(2- chloro-6 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin -4-yl] amino} pyridin-4-yl) methyl] (methyl) -A4-sulfanyliden} -2,2,2-trifluoroacetamide (575 mg; 1.15 mmol) in methanol (18.0 ml) and water (8.0 ml) to adjust the pH to 10.5. Oxone® (599 mg; 0.97 mmol) was added and the mixture was stirred at RT for 3.5 hours. During this time, the pH was maintained between 10-11, by 10 dropwise addition of an aqueous solution of potassium hydroxide (25%), if necessary. The mixture was filtered and the filter pad was washed with an excess of DCM. The pH of the filtrate was adjusted to 6-7 using an aqueous solution of hydrogen chloride (15%). The filtrate was washed with an aqueous solution of sodium chloride, followed by an aqueous solution of sodium thiosulfate (10%). The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (DCM to DCM / 10% ethanol) to give the desired product (180 mg; 0.43 mmol).

Example 5 and 6:

N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine enantiomers

Cl

image63

20 (rac) -N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine (163 mg) ) in enantiomers by preparative chiral HPLC.

 System:

 Agilent: Prep 1200, 2x Prep Pump, DLA, MWD, Prep FC

 Column:

 Chiralpak IC 5 pm 250x30 mm Nr.:021

 Solvent:

 MeCN / Diethylamine 100: 0.1 (v / v)

 Flow:

 50 ml / min

 Temperature:

 TA

 Solution:

 163 mg / 3.2 ml DMSO

 Injection:

 8 x 0.4 ml

 Detection:

 UV 254 nm

 Retention time in min purity in% yield Specific optical rotation:

 Example 5 Enantiomer 1

 5.4 - 7.7 min> 99% 61 mg (0.14 mmol) [a] D2U = 9.44 ° +/- 0.59 ° (DMSO, 589 nm, 20 ° C).

 Example 6 Enantiomer 2

 8.4-10.6 min 97.1% 64 mg (0.15 mmol) [a] D20 = -16.4 ° +/- 1.32 ° (DMSO, 589 nm, 20 ° C).

Example 7:

(rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine

5

image64

F

Preparation of Intermediary 7.1: (2-Chloro-6-methylpyridin-4-yl) methanol

N "" S

Cl

image65

OH

To a stirring solution of 2-chloro-6-methylpyridin-4-carboxylic acid (10.00 g; 55.4 mmol; Maybridge) in THF 10 (100 ml) at 0 ° C a solution of borane complex was added -tetrahydrofuran in 1M THF (221.5 ml; 221.5 mmol).

The mixture was allowed to react at RT overnight. Then, MeOH (22 ml) was added carefully to the stirred mixture by cooling with an ice bath. The batch was diluted with ethyl acetate and washed with aqueous sodium hydroxide solution (1N) and saturated aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (DCM / EtOH 15 95: 5) to give the pure product (7.24 g; 45.9 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 7.18 (s, 1H), 7.09 (s, 1H), 4.72 (d, 2H), 2.55 (s, 3H), 2, 17 (tr, 1H).

Preparation of Intermediary 7.2:

2-Chloro-6-methyl-4 - [(methylsulfanyl) methyl] pyridine

image66

To a stirring solution of (2-chloro-6-methylpyridin-4-yl) methanol (7.20 g; 45.7 mmol) in DMF (200 ml) at 0 ° C thionyl chloride was added dropwise (8.3 ml; 114.2 mmol). The mixture was allowed to react at 10 ° C for 2 hours. Then, the mixture was concentrated to give the crude product 2-chloro-4- (chloromethyl) -6-methylpyridine (17.08 g).

The crude 2-chloro-4- (chloromethyl) -6-methylpyridine (8.04 g) was dissolved in acetone (250 ml) and an aqueous solution of sodium methantiolate (21%, 18.3 ml, 54) was added , 8 mmol; Aldrich Chemical Company Inc.) drip on stirring. The mixture was stirred at RT for 3 hours before adding aqueous sodium methantiolate solution (21%, 15.3 ml, 45.7 mmol; Aldrich Chemical Company Inc.) and the mixture was stirred at RT overnight. Finally, more aqueous sodium methantiolate solution (21%, 15.3 ml, 45.7 mmol; Aldrich Chemical Company Inc.) was added and the mixture was

I stir at RT for 6 hours. The batch was diluted with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted twice with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (hexane to hexane / 20% ethyl acetate) to give the desired product (7.05 g; 37.6 mmol).

5 1H NMR (400 MHz, CDCls, 300K) 5 = 7.12 (s, 1H), 7.05 (s, 1H), 3.58 (s, 2H), 2.54 (s, 3H), 2 , 03 (s, 3H).

Intermediary Preparation 7.3:

5-Fluoro-4- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(methylsulfanyl) methyl] pyridin-2-yl} pyridin-2-amine

image67

F

A mixture of 6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine (1752 mg; 7.99 mmol, Intermediary 4.1), 2-chloro-6-methyl-4- 10 [(methylsulfanyl) methyl] pyridine (1000 mg; 5.33 mmol), chloro adduct (2-dicyclohexylphosphino-2 ', 4', 6'-tri-iso-propyl-1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) methyl-ferc-butyl ether (441 mg; 0.53 mmol; ABCR GmbH & CO. KG) and 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (254 mg; 0.53 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (5655 mg; 17.77 mmol) in toluene (111 ml) and NMP (15 ml) was stirred in an argon atmosphere at 130 ° C in a closed container for 4 hours. After cooling, the batch was diluted with ethyl acetate and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane to hexane / 50% ethyl acetate) to give the pure product (1600 mg; 4.32 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 8.87 (s, 1H), 8.07 (m, 1H), 7.99 (s, 1H), 7.74 (a, 1H), 7, 64 (s, 1H), 6.79 (m, 3H), 3.94 (s, 3H), 3.65 (s, 2H), 2.51 (s, 3H), 2.08 (s, 3H ).

20 Intermediary Preparation 7.4 .:

(rac) -2,2,2-Trifluoro-N - ([(2 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino | -6-methylpyridin-4-yl) methyl ] (methyl) -A4-

sulfanilidenjacetamide

image68

In an argon atmosphere, a solution of 2,2,2-trifluoroacetamide (687 mg; 6.07 mmol) in THF (2.8 ml) was added dropwise to a solution of sodium ferc-butoxide (389 mg ; 4.05 mmol) in THF (3.4 ml), such that the temperature of the mixture was kept below 10 ° C. Then, a freshly prepared solution of 1,3-dibromo-5,5-dimethylhydantoin (868 mg; 3.04 mmol) in THF (3.4 ml) was added dropwise to the stirred mixture, such that the temperature of the mixture was kept below 10 ° C. Then the mixture was stirred for 10 minutes at 10 ° C. Finally, a solution of 6- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4- 30 [(methylsulfanyl) methyl] pyridin-2-ylpyrimidin-4-amine (1500 mg; 4, 05 mmol) in dioxane (6 ml) and THF (3.0 ml) drip to the stirred mixture, such that the temperature of the mixture was kept below 10 ° C. The mixture was stirred for 75 minutes at 10 ° C. The batch was diluted with toluene (11.0 ml) with cooling and an aqueous solution of sodium sulphite (510 mg; 4.05 mmol in 11.0 ml water) was added such that the temperature of the mixture was maintained. below 15 ° C. The batch was extracted three times with ethyl acetate. The combined organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate 20% to 100%) to give the desired product (1310 mg; 2.72 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 8.88 (s, 1H), 8.12 (m, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7, 56 (a, 1H), 6.80 (m, 3H), 4.47 (d, 1H), 4.27 (d, 1H), 3.95 (s, 3H), 2.73 (s, 3H ), 2.53 (s, 3H).

40 Preparation of the final product:

An aqueous solution of potassium hydroxide (25%) was added dropwise to a stirring solution of (rac) -2,2,2-trifluoro-N - {[(2 - {[6- (4-fluoro-2) -methoxyphenyl) pyrimidin-4-yl] aminoj-6-methylpyridin-4-yl) methyl] (methyl) -A4-sulfanylidenjacetamide (400 mg; 0.83 mmol) in methanol (50 ml) and water (25 ml) for adjust the pH to 10.5. Oxone® (434 mg; 0.71 mmol) was added and the mixture was stirred at RT for 45 minutes. During this time, the pH was maintained between 10-11, for

drip addition of an aqueous solution of potassium hydroxide (25%), if necessary. The mixture was filtered and the filter pad was washed with an excess of DCM. The pH of the filtrate was adjusted to 6-7 using an aqueous solution of hydrogen chloride (15%). The filtrate was washed with an aqueous solution of sodium chloride, followed by an aqueous solution of sodium thiosulfate (10%). The organic layer was filtered using a Whatman filter and concentrated. The residue was digested with DCM and a few drops of ethanol, filtered and dried to give the desired product (153 mg; 0.38 mmol).

1H NMR (400 MHz, da-DMSO, 300K) 5 = 10.21 (s, 1H), 8.73 (s, 1H), 8.36 (s, 1H), 8.03 (m, 1H), 7.70 (s, 1H), 7.09 (m, 1H), 6.91 (m, 2H), 4.36 (m, 2H), 3.92 (s, 3H), 3.73 (s , 1H), 2.89 (s, 3H), 2.44 (s, 3H).

Example 8 and 9:

Enantiomers of 6- (4-fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine

image69

fifteen

(Rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine / 144 mg) in enantiomers by preparative chiral HPLC.

 System:

 Agilent: Prep 1200, 2x Prep Pump, DLA, MWD, Prep FC,

 Column:

 Chiralpak IC 5pm 250 x 20 mm

 Solvent:

 MeCN / MTBE 70:30 (v / v) + 0.1% DEA

 Flow:

 31 ml / min

 Temperature:

 TA

 Solution:

 144 mg / 3 ml DMSO / DMF 2: 1

 Injection:

 12 x 0.25 ml

 Detection:

 UV 280 nm

 Retention time in min purity in% yield

 Example 8 Enantiomer 1

 3.33-5.5 100 40 mg (0.10 mmol)

 Example 9 Enantiomer 2

 6.0 - 8.25 95.30 40 mg (0.10 mmol)

Example 10:

(rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyrimidin-4-

amine

image70

Intermediary Preparation 10.1: 2-Chloro-4 - [(methylsulfanyl) methyl] -6- (trifluoromethyl) pyridine

image71

4- (bromomethyl) -2-chloro-6- (trifluoromethyl) pyridine (1000 mg; 3.64 mmol; FCH Group Company) was dissolved in acetone 5 (40 ml) and an aqueous solution of sodium methantiolate (21 %, 1.2 ml, 3.64 mmol; Aldrich Chemical

Company Inc.) drip on stirring. The mixture was stirred at RT for 7 hours before diluting the batch with ethyl acetate and an aqueous solution of sodium chloride. The mixture was extracted twice with ethyl acetate. The combined organic layers were filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (hexane to hexane / 20% ethyl acetate) to give the desired product (716 mg; 2.96 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 7.61 (s, 1H), 7.50 (s, 1H), 3.70 (s, 2H), 2.06 (s, 3H).

Preparation of Intermediary 10.2:

6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(methylsulfanyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyrimidin-4-amine

image72

A mixture of 6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine (475 mg; 2.17 mmol, Intermediary 4.1), 2-chloro-4- [(methylsulfanyl) methyl] -6- (trifluoromethyl ) pyridine (349 mg; 1.44 mmol), chloro adduct (2-dicyclohexylphosphino-2 ', 4', 6'-tri-iso-propyl-1,1 '-biphenyl) [2- (2-aminoethyl) phenyl ] palladium (II) methyl-ferc-butyl ether (119 mg; 0.14 mmol; ABCR GmbH & CO. KG) and 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (69 mg; 0.14 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (1533 mg; 7.22 mmol) in toluene (30 ml) and NMP (4 ml) was stirred in an argon atmosphere at 130 ° C in a closed vessel during 4 hours. After cooling, the batch was diluted with DCM and washed with aqueous sodium chloride solution. The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (DCM to DCM / 5% EtOH) to give the pure product (550 mg; 1.30 mmol).

1H NMR (400 MHz, CDCls, 300K) 5 = 8.91 (s, 1H), 8.15 (s, 1H), 8.09 (m, 1H), 7.94 (s, 1H), 7, 74 (a, 1H), 7.35 (m, 1H), 25 6.81 (m, 2H), 3.95 (s, 3H), 3.74 (s, 2H), 2.09 (s, 3H).

Intermediary Preparation 10.3 .:

(rac) -2,2,2-Trifluoro-N - [{[2 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} -6- (trifluoromethyl) pyridin-4-

il] methyl} (methyl) -A4-sulfaniliden] acetamide

image73

In an argon atmosphere, a solution of 2,2,2-trifluoroacetamide (160 mg; 1.41 mmol) in THF (4 ml) was added dropwise to a solution of sodium ferc-butoxide (91 mg; 0 , 94 mmol) in THF (4 ml), such that the temperature of the mixture was kept below 10 ° C. Then, a freshly prepared solution of 1,3-dibromo-5,5-dimethylhydantoin (162 mg; 0.57 mmol) in THF (4 ml) was added dropwise to the stirred mixture, such that the temperature of the mixture was kept below 10 ° C. Then the mixture was stirred for 10 minutes 35 at 10 ° C. Finally, a solution of 6- (4-fluoro-2-methoxyphenyl) -N- {4 - [(methylsulfanyl) methyl] -6- was added

5

10

fifteen

twenty

25

(trifluoromethyl) pyridin-2-yl} pyrimidin-4-amine (400 mg; 0.94 mmol) in THF (4 ml) drip to the stirred mixture, such that the temperature of the mixture was kept below -5 ° C. The mixture was stirred for 2 hours at -5 ° C. The batch was diluted with toluene (4 ml) with cooling and an aqueous solution of sodium sulphite (119 mg; 0.94 mmol in 4 ml water) was added such that the temperature of the mixture was kept below 0 ° C. The batch was extracted three times with ethyl acetate. The combined organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (DCM to DCM / 5% EtoH) to give the desired product (204 mg; 0.38 mmol).

1H NMR (400 MHz, CDCl3, 300K) 5 = 8.92 (s, 1H), 8.42 (m, 1H), 8.14 (m, 1H), 7.85 (s, 1H), 7, 77 (s, 1H), 6.84 (m, 1 H), 6.78 (m, 1H), 4.48 (m, 2H), 3.95 (s, 3H), 2.79 (s, 3H).

Preparation of the final product:

An aqueous solution of potassium hydroxide (25%) was added dropwise to a stirring solution of (rac) -2,2,2-trifluoro-N - [{[2 - {[6- (4-fluoro-2 -methoxyphenyl) pyrimidin-4-yl] amino} -6- (trifluoromethyl) pyridin-4-yl] methyl} (methyl) -A4-sulfanyliden] acetamide (100 mg; 0.188 mmol) in methanol (2.5 ml) and water (1.5 ml) to adjust the pH to 10.5. Oxone® (98 mg; 0.16 mmol) was added and the mixture was stirred at RT for 6 hours. During this time, the pH was maintained between 10-11, by drip addition of an aqueous solution of potassium hydroxide (25%), if necessary. The mixture was filtered and the filter pad was washed with an excess of DCM. The pH of the filtrate was adjusted to 5-6 using an aqueous solution of hydrogen chloride (15%). The filtrate was washed with an aqueous solution of sodium chloride, followed by an aqueous solution of sodium thiosulfate (10%). The organic layer was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (32 mg; 0.07 mmol).

 System:

 Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001

 Column:

 XBrigde C18 5 pm 100x30 mm

 Solvent:

 A = H2O + 0.1% HCOOH

 B = MeCN

 Gradient:

 0-1 min B 1% B, 1-8 min B 1-99%, 8-10 min B 99%

 Flow:

 50 ml / min

 Temperature:

 TA

 Solution:

 Max. 250 mg / max 2.5 ml DMSO or DMF

 Injection:

 1 x 2.5 ml

 Detection:

 DAD scan range 210-400 nm

 EM IEN +, IEN-, scan range 160-1000 m / z

1H NMR (400 MHz, da-DMSO, 300K) 5 = 10.72 (s, 1H), 8.82 (m, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 8.03 (m, 1H), 7.54 (m, 1H), 7.11 (m, 1H), 6.93 (m, 1H), 4.58 (m, 2H), 3.94 (s , 1H), 3.90 (s, 3H), 2.93 (s, 3H).

Example 11:

(rac) -N- {4 - [(S-Ethylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

HN O '/, S

r ^^ N N

II II

N

or

image74

F

Intermediary Preparation 11.1:

N- {4 - [(Ethylsulfanyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

image75

A mixture of 4 - [(ethylsulfanyl) methyl] pyridin-2-amine (264 mg; 1.49 mmol; Enamine), 4-chloro-6- (4-fluoro-2- 5 methoxyphenyl) pyrimidine (300 mg; 1 , 19 mmol; Intermediary 1.1), chloro adduct (2-dicyclohexylphosphino-2 ', 4', 6'-tri-iso-propyl-1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (II ) methyl-ferc-butyleter (99 mg; 0.12 mmol; ABCR GmbH & CO. KG) and 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl (57 mg; 0.12 mmol; Aldrich Chemical Company Inc.) and potassium phosphate (1.26 g; 5.97 mmol) in toluene (27 ml) and NMP (2.1 ml) was stirred in an argon atmosphere at 130 ° C in a closed container for 4 hours. After cooling, the batch was diluted with DCM and washed with an aqueous solution of sodium chloride. The organic layer was filtered using a Whatman filter and concentrated. The residue was crystallized from ethanol to give the pure product (416 mg; 1.11 mmol).

1H NMR (400 MHz, DMSO-da): 5 [ppm] = 10.21 (s, 1H), 8.76 (d, 1H), 8.36 (s, 1H), 8.24 (d, 1H ), 8.04 (dd, 1H), 7.81 (s, 1H), 7.10 (dd, 1H), 6.97 (dd, 1H), 6.92 (td, 1H), 3.92 (s, 3H), 3.74 (s, 2H), 2.48-2.43 (m, 2H), 1.19 (t, 3H).

Intermediary Preparation 11.2:

15 (rac) -N- {Ethyl [(2 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methyl] -A4-sulfanyliden} -2, 2,2-

trifluoroacetamide

image76

In an argon atmosphere, a solution of 2,2,2-trifluoroacetamide (44 mg; 0.38 mmol) in THF (1 ml) was added dropwise to a solution of sodium ferc-butoxide (25 mg; 0, 25 mmol) in THF (1 ml), such that the temperature of the mixture was kept below 10 ° C. Then, a freshly prepared solution of 1,3-dibromo-5,5-dimethylhydantoin (43 mg; 0.15 mmol) in THF (1 ml) was added dropwise to the stirred mixture, such that the temperature of the mixture was kept below 10 ° C. Then the mixture was stirred for 10 minutes at -10 ° C. Finally, a solution of N- {4 - [(ethylsulfanyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine (100 mg; 0.25 mmol) was added in THF (1 ml) to the stirred mixture, such that the temperature of the mixture was kept below -10 ° C. The mixture was stirred for 50 minutes at -10 ° C. The batch was diluted with toluene (1 ml) with cooling and an aqueous solution of sodium sulphite (31.6 mg; 0.25 mmol in 1 ml water) was added such that the temperature of the mixture was kept below of 0 ° C. The batch was extracted three times with ethyl acetate. The combined organic layers were washed with an aqueous solution of sodium chloride, filtered using a Whatman filter and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / MeOH) to give the desired product (69 mg; 0.13 mmol).

1H NMR (400 MHz, DMSO-da): 5 [ppm] = 10.36 (s, 1H), 8.76 (d, 1H), 8.33 (d, 1H), 8.27 (s, 1H ), 8.05 (dd, 1H), 7.97 (s, 1H), 7.10 (dd, 1H), 6.98 (dd, 1H), 6.92 (trd, 1H), 4.64 -4.42 (m, 2H), 3.93 (s, 3H), 3.35-3.25 (m, 1H), 3.14-3.02 (m, 1H), 1.28 (tr , 3H).

Preparation of the final product:

35 (rac) -N- {Ethyl [(2 - {[6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-yl] amino} pyridin-4-yl) methyl] -A4-sulfanyliden} - 2,2,2-trifluoroacetamide (64 mg; 0.12 mmol) in methanol (10 ml). To this solution was added water (0.3 ml). A solution of Oxone® (95 mg: 0.15 mmol) in water (0.5 ml) was added to the first solution and the resulting mixture was stirred. The pH was maintained between 7.8-8.2 by the addition of an aqueous solution of potassium hydroxide (5%). After 30 and 60 minutes of reaction time additional portions of Oxone® (15 mg; 0.049 mmol each) were added. The pH was maintained between 7.8-8.2. After another 15 minutes of stirring the batch was diluted with water (100 ml). The suspension was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium sulphite (10%), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / MeOH) to give the desired product (48 mg; 0.12 mmol).

1H NMR (400 MHz, DMSO <L>): 5 [ppm] = 10.28 (s, 1H), 8.75 (d, 1H), 8.35 (s, 1H), 8.31 (d, 1H), 8.04 (dd, 1H), 7.86 (s,

1H), 7.10 (dd, 1H), 7.05 (dd, 1H), 6.92 (trd, 1H), 4.42-4.32 (m, 2H), 3.93 (s, 3H ), 3.72 (s, 1H), 2.99 (q, 2H), 1.26 (tr, 3H).

The following Table 1 provides an enumeration of the compounds described in the examples section:

Table 1

 Table 1

 Example No.

 Structure Compound Name

 one

 HN O f ^ N N ^ N O (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine

 2

 HN O f ^ N N ^ N O "6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S- methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine; enantiomer 1

 3

 HN O f ^ N N ^ N O ^ 6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine; enantiomer 2

 4

 Cl HN O N ^ N O "(rac) -N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

 5

 Cl HN O ^ N O ^ (+) - N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

 6

 Cl HN O r "NN ^ n O" (-) - N- {6-Chloro-4 - [(S- methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin -4-amine

 7

 HN O N N ^ N O (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine

 Table 1

 Example No.

 Structure Compound Name

 8

 HN O f ^ N Nl ^ N O 6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine; enantiomer 1

 9

 hn o \ N N ^ N O ^ 6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine; enantiomer 2

 10

 HN O ^ NO "(rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S- methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2- yl} pyrimidin-4- amine

 eleven

   (rac) -N- {4 - [(S-Ethylsulfonimidoyl) -methyl] pyridin-2-yl} - 6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine

Results:

Table 2: Inhibition for CDK9 and CDK2 of compounds according to the present invention

5 The IC50 values (inhibitory concentration at 50% of the maximum effect) are indicated in nM, "n.e." means that the compounds have not been evaluated in this test.

©: Example Number

©: CDK9: CDK9 / CycT1 kinase assay as described in Method 1a. of Materials and Procedures

10 ®: CDK2: CDK2 / CycE kinase assay as described in Method 2a. of Materials and

Procedures

©: CDK9 in high ATP: CDK9 / CycT1 kinase assay as described in Method 1b. of Materials and Procedures

© CDK2 in high ATP: CDK2 / CycE kinase assay as described in Method 2b. of Materials and 15 Procedures

Table 2

 ©

 © ® structure

 ©

 ©

 one

 HN O f ^ N ^^ N O ^ 5 600 49 1510

 ©

 © ® structure

 ©

 ©

 2

 HN O f ^ N N ^ N O "" 9 1300 30 1540

 3

 HN ^^ N N ^ N O ^ 4 660 10 1040

 4

 Cl HN O f ^ N N ^ N O 4 160 11 1130

 5

 Cl hn o N N ^ N O "5 56 9 1420

 6

 Cl HN O f ^ N N ^ N O ^ 4 94 5 1820

 7

 HN O f ^ N ^ N O "5 280 4 3630

 8

 HN O f ^ N ^ N O "4 400 6 6330

 9

 HN O N N ^ N O "4 330 2 4400

 ©

 © ® structure

 ©

 ©

 10

 R ^ F HN O N ^ N O ^ 5 63 3 797

 eleven

 HN O f ^ N N ^ N O ^ n.e. n.e. 194 n.a.

5

10

fifteen

 Cellphone line

 Source Indication

 HeLa

 ATCC Human cervical tumor

 NCI-H460

 ATCC Human non-small cell lung carcinoma

 A2780

 ECACC Human ovarian carcinoma

 DU 145

 ATCC Human hormone independent prostate carcinoma

 HeLa-MaTu-ADR

 EPO-GmbH Berlin Multi-drug resistant cervical carcinoma

 Caco-2

 ATCC Human Colorectal Carcinoma

 B16F10

 ATCC Mouse Melanoma

 MOLM-13

 DSMZ Human acute myeloid leukemia

Tables 3a and 3b: Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2, B16F10, A2780 and MOLM 13 cells by compounds according to the present invention, determined as described in the Method 3. Materials and Procedures. All IC50 values (inhibitory concentration at 50% of maximum effect) are indicated in nM, "n.e." means that the compounds have not been evaluated in this test.

©: Example Number ©: Inhibition of HeLa ® cell proliferation: Inhibition of HeLa-MaTu-ADR © cell proliferation: Inhibition of NCI-H460 cell proliferation ©: Inhibition of DU145 cell proliferation ©: Inhibition of cell proliferation Caco-2 ©: B16F10 ® cell proliferation inhibition: A2780 ® cell proliferation inhibition MOLM cell proliferation inhibition 13

_____________________ Table 3a: Indications represented by cell lines _____________________

Table 3b: Inhibition of proliferation

 ©

 Structure © ® © © © ©

 one

 HN O f ^ N N ^ N O "" 477 335 638 309 537 488 60 n.a.

 2

 HN O f ^ N N ^ N O "456 n.e. n.e. n.e. n.e. n.e. 193 189

 3

 HN O n ^ n O ^ 850 n.e. n.e. n.e. n.e. n.e. 126 80

 4

 Cl hn o r'N n ^ n O ^ 109 97 372 77 145 215 62 47

 5

 Cl HN O f'N Nl ^ N O ^ 104 109 185 105 166 122 34 33

 6

 Cl HN O N N ^ N O "" 104 111 192 110 177 123 39 44

 7

 HN O N N ^ N O "" 121 217 375 121 230 216 35 53

 ©

 Structure © © © © © © ® ®

 8

 HN or rN N ^ N O; 's "^^ n ^^ 118 112 319 179 246 284 36 64

 9

 HN O N N ^ N O "52 178 193 126 212 205 39 43

 10

 hn ^ i "n N ^ N or 60 104 135 88 116 100 32 32

 eleven

 HN O f ^ N ^^ N O ^ 338 n.e. n.t n.t n.t n.t n.t n.t

Table 4: Thermodynamic solubility of compounds according to the present invention in water at pH 6.5 as determined by the equilibrium stirring flask procedure described in Method 4. of Materials 5 and Procedures.

©: Example Number ©: Solubility in mg / l in water at pH 6.5.

©: Solubility in mg / l in citrate buffer pH4

Table 4

 ©

 Structure

 ©

 ©

 one

 HN O f ^ N N ^ N O ^ 7 n.e.

 4

 Cl HN O f "N ^ N O" n.e. fifteen

 ©

 Structure ©

 7

 HN O i'N Nl ^ N O n.e. 157

 10

 F-, F HN O N ^ N O "n.e. 11

Table 5: Caco-2 permeability of compounds according to the present invention, determined as described in Method 5. of Materials and Procedures.

5

10

©: Example Number

©: Concentration of the evaluated compound indicated in pM. ®: Papp A-B (Mari) indicated in [nm / s]

©: Papp B-A (Mari) indicated in [nm / s]

©: Output relationship

Table 5

 ©

 © ® structure

 ©

 ©

 one

 HN O f ^ N N ^ N O "2 26 243 9.3

 7

 HN O f ^ N Ni ^ N O ^ 2 39 289 7.49

 10

 HN or f ^ N n ^ N O ^ 2 45 206 4.58

Table 6: Inhibition of carbonic anhydrase-1 and carbonic anhydrase-2 as determined by the carbonic anhydrase assay as described in Method 6. of Materials and Procedures.

©: Compound Number

15 ©: Carbonic anhydrase inhibition-1: IC50 values (50% inhibitory concentration of the effect

maximum) are indicated in nM.

® Carbonic anhydrase-2 inhibition: IC50 values (50% inhibitory concentration of maximum effect) are indicated in nM.

Table 6

 ©

 © ® structure

 one

 HN O f ^ N N ^ N O ""> 10000> 10000

5

Claims (15)

5 10 fifteen 1. A compound of general formula (I) R3 5 R R — N O \\ // ^ S R1 ^ image 1 N 'R2 (I) in which R1 represents a group selected from C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, phenyl-C1-C3 alkyl- or heteroaryl-C1-C3 alkyl-, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-C1-C3 alkyl-, C1-C6 alkoxy-, C1 fluoroalkoxy -C3-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, - OP (O) (OH) 2, -C (O) OH, -C (O) NH2; R2 represents a group selected from , R ° OR image2 -R6 image3 R ' image4 R6 R ' image5 image6 R6 R ' OR image7 OR R6 image8 R ' OR image9 OR R6 image10 R ' F F R3, R4 independently represent each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, cyano, C1-C3 alkyl, C1-C3 alkoxy, halo -C1-C3 alkyl-, C1-C3 fluoroalkoxy; R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9, - C (O) NR10R11, -P (O) (OR12) 2 , -CH2OP (OR12) 2, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C1-C6- alkyl group, C3-C7- cycloalkyl, heterocyclyl-, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R6, R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl; C1-C3 fluoroalkoxy; R8 represents a group selected from 5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 a) a C1-C6 alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N -acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-, C2-C3 alkenyl-, C2-C3- alkynyl, C3- cycloalkyl C7-, heterocyclyl-, phenyl, heteroaryl, wherein said C3-C7- cycloalkyl-, heterocyclyl-, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, alkyl C1-C3-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; b) a C3-C7- cycloalkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino- , N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2- alkynyl C3-; c) a heterocyclyl- group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3- alkoxy, C2-C3 alkenyl, C2-C3 alkynyl; d) a phenyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; e) a heteroaryl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl -N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; f) a phenyl-C1-C3-alkyl group, wherein the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino -, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; g) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, -NH2, alkylamino -, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; h) a C3-C6-cycloalkyl-C1-C3-alkyl group, wherein the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-alkyl C3-, C1-C3- alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy; i) a heterocyclyl-C1-C3-alkyl group, wherein the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-C3 alkyl-, C1-C3 alkoxy- , halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R9 represents a group selected from C1-C6- alkyl, halo-C1-C3- alkyl, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino- , N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R10, R11 independently represent each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl, wherein said C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl, phenyl, benzyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl -, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl- N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, or R10 and R11 , together with the nitrogen atom to which they are attached, they form a cyclic amine; R12 represents a group selected from hydrogen, C1-C4 alkyl- or benzyl, and enantiomers, diasteromers, salts, solvates or solvate salts thereof. 2. The compound of general formula (I) according to claim 1, wherein R1 represents a group selected from C1-C6- alkyl, C3-C5- cycloalkyl, wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C3 alkoxy, halo-C1-C2 alkyl-, C1-C2 fluoroalkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines , -OP (O) (OH) 2, -C (O) OH, -C (O) NH2; R2 represents a group selected from 5 10 fifteen twenty 25 30 35 40 Four. Five fifty image11 -R ° R R R ' R ' R3 represents a hydrogen atom, a fluorine atom or a chlorine atom, a C1-C3 alkyl group or a halo-C1-C3 alkyl group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -S (O) 2R9, - C (O) NR10R11, -P (O) (OR12) 2 , -CH2OP (OR12) 2, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl-, phenyl, heteroaryl, wherein said C1-C6- alkyl group, C3-C7- cycloalkyl, heterocyclyl-, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R6, R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom, a chlorine atom, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl; C1-C3 fluoroalkoxy; R8 represents a group selected from a) a C1-C6- alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, amines cyclic, cyano, C1-C3- alkyl, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy, C1-C3 alkoxy, C3-C7 cycloalkyl, heterocyclyl, phenyl, heteroaryl, wherein said C3-C7 cycloalkyl group -, heterocyclyl, phenyl or heteroaryl is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, dialkylamino-, acetylamino-, N- methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; b) a phenyl-C1-C3-alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy; c) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, dialkylamino-, acetylamino -, N-methyl-N-acetylamino-, cyclic amines, cyano, C1-C3 alkyl-, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy; d) a C3-C6-cycloalkyl-C1-C3-alkyl group, wherein the C3-C6-cycloalkyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C1-alkyl C3-, C1-C3- alkoxy, halo-C1-C3- alkyl, C1-C3 fluoroalkoxy; e) a heterocyclyl-C 1 -C 3 alkyl group, wherein the heterocyclyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy , halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R9 represents a group selected from C1-C6- alkyl, halo-C1-C3- alkyl, C3-C7- cycloalkyl, heterocyclyl-, phenyl, benzyl or heteroaryl, wherein said group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl-, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino- , N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy; R10, R11 independently represent each other, a group selected from hydrogen, C1-C6 alkyl-, C3-C7- cycloalkyl, heterocyclyl, benzyl, phenyl or heteroaryl, wherein said C1-C6- alkyl, C3-C7- cycloalkyl, heterocyclyl, benzyl, phenyl or heteroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, C1-C3 alkyl -, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy, or R10 and R11 , together with the nitrogen atom to which they are attached, they form a cyclic amine; R12 represents a group selected from hydrogen or C1-C4- alkyl, and enantiomers, diasteromers, salts, solvates or solvate salts thereof. 3. The compound of general formula (I) according to claim 1, wherein R 1 represents a C 1 -C 6 alkyl or C 3 -C 5 cycloalkyl group, wherein said group is optionally substituted with a substituent selected from the group consisting of hydroxy, C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino-, cyclic amines, -OP (O) (OH) 2; 5 10 fifteen twenty 25 30 35 40 R2 represents a group selected from image12 R3 represents a hydrogen atom, a fluorine atom or a chlorine atom, a C1-C3 alkyl group or a C1-C3 fluoro-alkyl group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11, -P (O) (OR12) 2, -CH2OP (OR12) 2 or C1-C3- alkyl, wherein said C1-C3 alkyl group is optionally substituted with a substituent, selected from -NH2, alkylamino-, dialkylamino- or cyclic amines; R6, R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom; R8 represents a group selected from a) a C1-C3- alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from halogen, halo-C1-C3 alkyl; b) a phenyl-C1-C3-alkyl group, where the phenyl group thereof is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, C1-C3 alkyl -, halo-C1-C3 alkyl-, C1-C3 fluoroalkoxy-, C1-C3 alkoxy-; c) a heteroaryl-C1-C3-alkyl group, wherein the heteroaryl group thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, cyano, C1-C3- alkyl, halo-C 1 -C 3 alkyl, C 1 -C 3 fluoroalkoxy, C 1 -C 3 alkoxy; R9 represents a group selected from C1-C3-alkyl, halo-C1-C3-alkyl, or a benzyl group, where the phenyl group thereof is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, -NH2, alkylamino-, dialkylamino; R10, R11 independently represent each other, a group selected from hydrogen, C1-C3- alkyl, benzyl, or R10 and R11, together with the nitrogen atom to which they are attached, form a cyclic amine; R12 represents a group selected from hydrogen or C1-C2- alkyl, and enantiomers, diasteromers, salts, solvates or solvate salts thereof. 4. The compound of general formula (I) according to claim 1, wherein R1 represents a C1-C6 alkyl group, wherein said group is optionally substituted with a substituent, selected from the group consisting of C1-C3 alkoxy-, -NH2, alkylamino-, dialkylamino- or cyclic amines; R2 represents a group selected from image13 R3 represents a hydrogen atom, a fluorine atom or a chlorine atom, or a methyl or trifluoromethyl group; R4 represents a hydrogen atom or a fluorine atom; R5 represents a group selected from a hydrogen atom, cyano, -C (O) R9, -C (O) OR9, -C (O) NR10R11; R6, R7 independently represent each other, a group selected from a hydrogen atom, a fluorine atom or a chlorine atom; R8 represents a C1-C3- alkyl group; 5 10 fifteen twenty 25 30 35 40 R9 represents a C1-C3- alkyl group, a benzyl or trifluoromethyl group; R10, R11 represent, independently from each other, a group selected from hydrogen, C1-C2- alkyl; and enantiomers, diasteromers, salts, solvates or solvate salts thereof. 5. The compound of general formula (I) according to claim 1, wherein R1 represents a C1-C3- alkyl group; R2 represents a group image14 R3 represents a hydrogen atom or a chlorine atom, or a methyl or trifluoromethyl group; R4 represents a hydrogen atom; R5 represents a hydrogen atom; R6 represents a fluorine atom; R7 represents hydrogen; R8 represents a methyl group; and enantiomers, diasteromers, salts, solvates or solvate salts thereof. 6. The compound of general formula (I) according to claim 1, wherein R1 represents a methyl or ethyl group; R2 represents a 4-fluoro-2-methoxyphenyl group; R3 represents a hydrogen atom or a chlorine atom, or a methyl or trifluoromethyl group; R4 represents a hydrogen atom; R5 represents a hydrogen atom; and enantiomers, diasteromers, salts, solvates or solvate salts thereof. 7. The compound according to claim 1, which is - (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine; - 6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 1; - 6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 2; - (rac) -N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine; - N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine, enantiomer 1; - N- {6-Chloro-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine, enantiomer 2; - (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine; - 6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 1; - 6- (4-Fluoro-2-methoxyphenyl) -N- {6-methyl-4 - [(S-methylsulfonimidoyl) methyl] pyridin-2-yl} pyrimidin-4-amine, enantiomer 2; - (rac) -6- (4-Fluoro-2-methoxyphenyl) -N- {4 - [(S-methylsulfonimidoyl) methyl] -6- (trifluoromethyl) pyridin-2-yl} pyrimidin-4-amine; - (rac) -N- {4 - [(S-Ethylsulfonimidoyl) methyl] pyridin-2-yl} -6- (4-fluoro-2-methoxyphenyl) pyrimidin-4-amine, and enantiomers, diasteromers, salts, solvates or solvate salts thereof. 8. A compound of general formula (I) according to any one of claims 1 to 7, for use in the treatment and / or prophylaxis of hyperproliferative disorders, infectious diseases induced by viruses and / or diseases cardiovascular 9. A compound of general formula (I) according to any one of claims 1 to 7, for use in the treatment and / or prophylaxis of lung carcinomas, prostate carcinomas, cervical carcinomas, colorectal carcinomas, melanomas, carcinomas of ovary and leukemia. 10. A pharmaceutical combination comprising a compound according to any one of claims 1 to 7, in combination with at least one or more additional active ingredients. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, in combination with an inert, non-toxic and pharmaceutically acceptable adjuvant. 12. The pharmaceutical combination according to claim 10, for use in the treatment and / or prophylaxis of hyperproliferative disorders, infectious diseases induced by viruses and / or cardiovascular diseases. 13. The pharmaceutical composition according to claim 11, for use in the treatment and / or prophylaxis of hyperproliferative disorders, of virus-induced infectious diseases and / or of cardiovascular diseases. 14. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 7, a process in which a compound of formula (6) is oxidized, wherein R1, R2, R3 and R4 are as defined for the compound of formula (I) according to any one of claims 1 to 6, F image15 H 2 6 10 with an alkaline salt of permanganic acid to an aliphatic ketone of formula C1-C2-C (O) -C1-C2 alkyl as solvent, followed, if the trifluoroacetyl group present in the compounds of formula (6) has not been removed by cleavage during the oxidation process mentioned above, from the removal of said trifluoroacetyl group by treatment of the resulting intermediate with a suitable base in a alcoholic solvent, to give a compound of formula (I), in which R5 is hydrogen, R HN O \\ //, S R ' R3 image16 N R2 (I); R5 = H and process in which the resulting compound optionally, if appropriate, is converted with the corresponding (i) solvents and / or (ii) bases or acids to solvates, salts and / or solvates of salts thereof . 15. A process for the preparation of a compound of formula (I), according to any one of claims 1 to 7, a process in which a compound of formula (6) is oxidized, wherein R1, R2, R3 and R4 are as defined for the compound of formula (I) according to any one of claims 1 to 6, F image17 N ' N N R I H 6 with a peroxomonosulfate-based oxidant in a solvent that is selected from an aliphatic alcohol of formula C1-C3-alkyl-OH, water and N, N-dimethylformamide, or a mixture thereof, to give a compound of formula (I ) in which R5 is hydrogen, R R HN O \\ // I / S R3 image18 ‘R2 (I); R5 = H 5 and process in which the resulting compound optionally, if appropriate, is converted with the corresponding (i) solvents and / or (ii) bases or acids to solvates, salts and / or solvates of salts thereof.